Medicinal Chemistry Complete Notes

Doctor of Pharmacy, Final Professional
CHEMISTRY
Ghulam Murtaza Hamad
Punjab University College of Pharmacy, Lahore, Pakistan
Session 2016-2021

GM Hamad
Table of Contents
01 Introduction to Medicinal Chemistry 01
02
Drug Targets and Drug Designing
a. Introduction and types of Drug Targets
b. Introduction to molecular Modelling and Computational
Chemistry
c. Structure Based Designing
d. Ligand Based Designing
e. Various Techniques in Drug Synthesis
43
46
51
54
55
03
General Properties, Chemistry, Biological Action, Structure
Activity Relationship and Therapeutic Applications of the
following:
a. Hormones
b. Anti-neoplastic Agents
c. Sedatives and Hypnotics
d. Anesthetics
e. Analgesics and Antipyretics
f. Sulphonamides
g. Antimalarials
h. Diuretics
i. Antitubercular Drugs
j. Antiviral Drugs
k. Immunosuppressant Agents
l. Antibiotics
59
80
97
109
126
144
152
179
196
217
226
234
04 Past Papers 261
05 Viva Questions 265
06 References 269

Chapter 1 – Introduction to Medicinal Chemistry
GM Hamad
INTRODUCTION TO MEDICINAL CHEMISTRY
BASIC TERMS USED IN MEDICINAL CHEMISTRY
MEDICINAL CHEMISTRY
“It is a chemistry-based discipline concerned with the invention, discovery,
design, identification and preparation of biologically active compounds, the
study of their metabolism, the interpretation of their mode of action at the
molecular level and construction of structure activity relationships.”
DRUG
“A chemical substance or material other than food that is intended for
application in diagnosis, prevention, mitigation, treatment and cure of the
disease in animal or human being is called drug.”
DRUG DESIGN
“It is an inventive process in which computational modeling techniques and
bioinformatics approaches are used to construct molecules that are
complementary in shape and charge to the molecular target with which they
bind and interact.”
DRUG DISCOVERY
”Drug discovery is a systematic approach which involves setting up of a
working hypothesis of the biological target for a particular disease, establishing
suitable models for estimation of biological activities and screening of large
libraries of molecules to identify active compounds.
DRUG DEVELOPMENT
”Drug development takes into account the pre-clinical and clinical studies on
the biologically active compounds obtained from the discovery process and its
regulatory approval by national authority such as US Food and Drug Regulatory
Authority (US-FDA).”
LEAD COMPOUNDS (DEVELOPMENTAL CANDIDATES)
“A chemical compound or compound series that have desired but non-
optimized biological activity are called lead compounds.”
Or
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“A chemical compound or compound series that satisfy predefined minimum
criteria – appropriate stereo-electronic, physicochemical, pharmacokinetic and
toxicological properties for clinical usefulness, selectivity against chosen
molecular target and tractable structure activity relationship – but have
suboptimal structure that requires modifications to improve the selectivity,
potency, and/or pharmacokinetic and toxic properties are called lead
compounds.”
LEAD DISCOVERY
“Lead discovery refers to a process of identifying lead compounds.”
LEAD GENERATION
“Lead generation refers to the strategies developed to generate lead
compounds.”
LEAD OPTIMIZATION
“Lead optimization refers to the synthetic modification of lead compounds.”
LEAD VALIDATION
“Lead validation is a process of authenticating a lead compound i.e. confirming
the expected physicochemical, pharmacological, pharmacokinetic and toxic
properties through experiments.”
STRUCTURE ACTIVITY RELATIONSHIP (SAR)
“It is the relationship between chemical structure and pharmacological activity
for a series of compounds.”
QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS (QSAR)
“Quantitative structure-activity relationships are the mathematical equations –
derived through regression and pattern recognition techniques – that link
chemical structure and pharmacological activity of a series of compounds in a
quantitative manner.”
2-DIMENSIONAL QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS (2D-
QSAR)
“2D-QSAR is an approach to establish a mathematical relationship between
biological activity of a series of compounds and their measurable
physicochemical parameters that are believed to influence biological activity.”
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3-DIMENSIONAL QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS (3D-
QSAR)
“3D-QSAR is an approach to establish a mathematical relationship between
biological activity and 3-dimensional structure of a series of compounds that is
believed to influence biological activity.”
REGRESSION ANALYSIS
“Regression analysis is a group of mathematical methods used to obtain
equations relating different sets of data. The data are fed into a suitable
computer program, which, on execution, produces an equation that represents
the line that is the best ﬁt for those data.”
y = mx + c
y = parameter along y-axis, m = slope, x = parameter along x-axis and c = y-
intercept.
PATTERN RECOGNITION
“Pattern recognition refers to the identification or classification of patterns in
large data sets using appropriate mathematical and statistical methodologies.”
STRUCTURE-PROPERTY CORRELATIONS
“Structure-property correlations are the statistical methods used to correlate
any structural property to intrinsic, chemical or biological property.”
NEW CHEMICAL ENTITY (NCE)
“A new chemical entity or new molecular entity is a drug that contains no
active moiety previously approved for use by the national drug regulatory
authority.”
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INVESTIGATIONAL NEW DRUG (IND)
“An investigational new drug is a compound that is not yet approved for
general use by the national authority but undergoing clinical investigations to
assess its safety and efficacy.”
MOLECULAR TARGET (BIOLOGICAL TARGET)
“A molecular target is a protein (receptor, enzyme or ion-channel) or nucleic
acid (RNA or DNA) that is involved in manifestation of a clinical disorder or
propagation of any untoward event. During drug discovery process, the first
step is to obtain the biochemical, physiological, pharmacological or genomic
information of the molecular target that supports its role in a disease.”
PRIVILEGED STRUCTURE
“It refers to the substructural features – semi-rigid scaffold presenting multiple
hydrophobic residues without undergoing hydrophobic collapse – that confer
desirable (drug-like) properties in compounds containing that feature.”
DRUG-LIKELINESS
“Drug likeliness is a complex balance of various molecular and structural
properties (molecular weight, shape, electronic distribution, polar surface area,
log P, reactivity, hydrogen bond donors/acceptors, dissociation constant and
pharmacophore) which determine, whether a particular compound is similar to
known drugs or not. These features are important predictors of its
physicochemical, biochemical, pharmacokinetic and toxic properties of a drug.”
DRUG-LIKE COMPOUND
“A compound is considered to be drug-like, if it possesses acceptable ADME and
toxicity properties to survive through the human Phase-I trials.”
PHARMACOPHORE
“A pharmacophore is the group of steric and electronic features that is
necessary to ensure the optimal supramolecular interactions with a specific
biological target structure and to trigger or block its biological response.”
A pharmacophore does not represent a real molecule or a real association of
functional groups, but a purely abstract concept that accounts for the common
molecular interaction capacities of a group of compounds toward their target
structure. The pharmacophore can be considered as the largest common
denominator shared by a set of active molecules.
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PHARMACOPHORIC DESCRIPTORS
“These are the descriptors that define a pharmacophore such as hydrogen
bonding, hydrophobic and electrostatic interaction sites due to the constituent
atoms, ring centers and virtual points.”
PATENTABILITY
“It refers to the set of criteria – suitability, novelty, inventiveness, utility and an
adequate description – that must be satisfied to achieve commercial exclusivity
for an invention.”
ANALOGUE
“Chemical compounds that have structural similarity to a reference compound
but display different chemical and/or biological properties. During drug
development, a number of analogues of lead compounds are synthesized for
SAR studies.”
ATTRITION RATE (HIGH FAILURE RATE)
”It refers to the rate of loss of candidates during progression through the drug
development and optimization phases.”
BACK-UP COMPOUND:
”It is a molecule – pharmacologically equivalent to lead but has significant
structural differences – selected as a replacement for lead drug candidate if it
fails during pre-clinical and clinical studies.”
BEST-IN-CLASS
“It is a drug that acts on a specific molecular target that provides the best
balance between efficacy and adverse effects.”
BIOASSAY
“It is procedure for determination of the concentration, purity, and/or
biological activity of a substance (vitamin, hormone, plant growth factor, drug,
enzymes) by measuring its effect on an organism, tissue, cell and enzyme or
receptor preparation and comparing them with a standard.”
BIOINFORMATICS
“It is a discipline that encompasses the development and utilization of
computational tools such as databases and data management tools to
integrate, presentation tools to comprehend, and algorithms to extract
meaning and useful information from large amounts of heterogeneous
biological data.”
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CHEMICAL DATABASE
“A chemical database is a specific electronic repository for storing and
retrieving chemical information.”
CHEMICAL LIBRARY
“A collection of compounds which represent expansion around a single core
structure or scaffold produced through combinatorial synthesis and is available
for biological screening.”
clogP
“It is the calculated value of octanol/water partition coefficient used for
structure-property correlation and QSAR studies.”
CLUSTER
“It is a group of compounds that are structurally, physicochemically or
biologically related. Organizing a set of compounds into clusters is often used
to assess diversity or develop SAR models.”
COMPARATIVE MOLECULAR FIELD ANALYSIS (COMFA)
“It is a 3D-QSAR method that uses statistical correlation techniques for the
analysis of the quantitative relationship between the biological activities of a
set of compounds with a specific alignments, and their three dimensional
electronic and steric properties. “
CONGENER
“Substances that are structurally related to each other and linked by origin or
function are called congeners.”
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RECEPTORS
DEFINITION
“A receptor is a macromolecule that specifically recognizes and binds a ligand
and, transduces and integrates the signal received from it into biological
systems.”
CHEMISTRY
The majority of receptors are;
 Proteins (amino acid polymers)
 Glycoproteins
STRUCTURE
C-TERMINAL
 The C-terminus is the free carboxylic group (-COOH) located at one end of
a polypeptide chain or protein.
N-TERMINAL
 The N-terminus is the free amino group (-NH2) located at one end of a
polypeptide chain or protein.
LIGAND-BINDING DOMAIN
 The region on a receptor where a ligand binds to elicit, block or
attenuate a biological response is known as the ligand binding domain or
ligand binding site.
ALLOSTERIC BINDING DOMAIN
 A binding site other than the one used by the endogenous ligand is
called allosteric binding domain.
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DUAL BINDING DOMAIN
 It refers to the presence of two distinct ligand-binding domains on the
same receptor.
CLASSIFICATION
ON THE BASIS OF LOCATION
I. CELL SURFACE RECEPTORS
 These receptors are embedded in the lipid membrane of cells.
SYNONYMS
 Transmembrane receptors
COMPONENTS
 Each cell-surface receptor has three main components:
An external ligand-binding domain
A hydrophobic membrane-spanning region
An intracellular domain inside the cell
LIGANDS
 Large molecular weight substances (peptides)
 Highly polar substances or charged species (catecholamines)
FUNCTION
 Signal transduction (receive message from extracellular ligand and
convert it to intracellular signal).
EXAMPLES
 Ion channel-linked receptors (ionotropic receptors)
 G protein-linked receptors (metabotropic receptors)
 Enzyme-linked receptors
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II. INTRACELLULAR RECEPTORS
 These receptors are found inside the cell.
SYNONYMS
 Internal receptors
LIGANDS
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 Small molecular weight substances
 Hydrophobic (lipid-soluble) compounds
EXAMPLES
 Cytoplasmic receptors
 Nuclear receptors
ON THE BASIS OF FUNCTION
 According to functions, receptors are divided into four superfamilies.
The members of each superfamily have same general structure and
mechanism of action but may vary in the sequence of amino acid residue
in certain regions and sizes of extracellular and intracellular domains.
I. SUPERFAMILY 1
TYPE
 Cell-surface receptors
SYNONYM
 Ion channel-linked receptors
STRUCTURE
 -C and -N terminus in the extracellular fluid
 Sugar is attached to extracellular –N terminal chain
 4-5 membrane-spanning subunits (2 α, 1 β, 1γ and 1 δ) surrounding a
central pore
 Each membrane-spanning subunit contains 20-25 amino acid residues
arranged in an α-helix
LIGANDS
 Fast neurotransmitters (nicotine, acetylcholine, gamma amino butyric
acid, glutamate)
EFFECTOR
 Ion channels
ACTIVATION
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 Two molecules of ligand upon binding to the α-subunits activate the
receptor that cause opening of the central pore and consequently
passage of ions in and out of a cell.
EXAMPLES
 Nicotine acetylcholine (nAChR) receptor
 Gamma amino butyric acid (GABAA) receptor
 Glutamate receptor
II. SUPERFAMILY 2
TYPE
SYNONYM
 G-protein coupled receptors
STRUCTURE
 Single polypeptide chain containing 400-500 amino acid residues
 -N terminus lies in the extracellular fluid
 -C terminus lies in the intracellular fluid
 7 membrane-spanning subunits surrounding a central pocket containing
receptor site
 Each membrane-spanning subunit contains 20-25 amino acid residues
arranged in an α-helix
 Intracellular domain is attached with an effector protein called G-protein
LIGANDS
 Slow transmitters (epinephrine, dopamine and serotonin)
EFFECTOR
 Ion channel
 Enzymes
ACTIVATION AND SIGNAL TRANSDUCTION
 The binding of ligand to the receptor site causes conformational change
in the intracellular polypeptide loop and C-terminus chain. These
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changes attract G-protein associated with intracellular domain of the
receptor.
 G-Proteins are a family of unattached proteins that diffuse through the
cytoplasm. They consist of three polypeptide subunits (α, β and γ). In
resting state, guanosine diphosphate (GDP) is bound to α subunit of the
G-protein. Upon activation, GDP at α subunit of G-protein is exchanged
for GTP. The activated subunit detaches from the protein and migrates
to either the receptor of an ion channel or the active site of an enzyme.
The coupling of α -GTP subunit to the receptor of the ion channel opens
or closes the channel, and to the enzyme inhibits or activates it.
 The action of α -GTP subunit is terminated when the GTP is hydrolyzed
to GDP by the catalytic action of α subunit.
EXAMPLES
 Muscarinic acetylcholine (mAChR) receptor
 Noradrenergic receptor
III. SUPERFAMILY 3
TYPE
SYNONYM
 Enzyme-linked receptors
STRUCTURE
 -N terminus in the extracellular fluid
 -C terminus in the intracellular fluid
 Single helical transmembrane subunit
 Intracellular domain contains tyrosine kinase residue, an ATP binding
site near the surface of membrane and substrate site near the end of
domain.
LIGANDS
 Insulin
 Growth factors
EFFECTOR
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 Intracellular proteins and enzymes
ACTIVATION
 Binding of ligand causes dimerization of receptor and subsequent
conformational changes which trigger the autophosphorylation of
tyrosine residues in the intracellular domain. The phosphorylated
residues attract and bind to intracellular proteins and lead to biological
responses.
EXAMPLES
 Insulin receptors
 Cytokine receptors
IV. SUPERFAMILY 4
TYPE
 Intracellular receptors
SYNONYM
STRUCTURE
 Large proteins with 400-1000 amino acid residues
 Central section of the protein contains two loops having 15 residues.
These loops are called zinc fingers since they originate from a group of 4
cysteine residues coordinated to a zinc atom.
 Hormone receptor lies on C-terminal side
 N-terminal controls the gene transcription
LIGANDS
 Steroidal hormones
 Thyroid hormones
 Retinoic acid
 Vitamin D
EFFECTOR
 Gene transcription
ACTIVATION
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 Conformational changes caused by the binding of the hormone to the
receptor expose the DNA binding domain, which is normally hidden
within the structure of the protein. This allows the DNA to bind to the
protein, an increase in RNA polymerase activity and production of a
speciﬁc mRNA. This mRNA controls the synthesis of a speciﬁc protein
that produces the cellular response.
EXAMPLES
 Glucocorticoid receptors
 Antidiuretic hormone receptors
 Vasopressin receptors
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LIGAND
DEFINITION
 Any endogenous or exogenous chemical agent (ion or molecule) that
binds to a receptor to elicit, block or attenuate a biological response is
known as a ligand or molecular messenger.
EXAMPLES
 Neurotransmitter
 Hormone
 Lymphokines
 Lectin
 Microbes (viruses, bacteria)
 Toxins
 Drugs
AUTORECEPTOR
 It is a receptor present at a nerve ending that regulates, via positive or
negative feedback processes, the synthesis and/or release of its own
physiological ligand.
ORPHAN RECEPTOR
 It is a receptor for which an endogenous ligand has yet to be identified.
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SIGNAL TRANSDUCTION
DEFINITION
 Signal transduction refers to the series of molecular events that take
place when a ligand binds to cell-surface receptor and the message
carried by it is transmitted through the cell to evoke an appropriate
response.
SIGNALING MOLECULES
 These are the molecules that transmit the message produced by ligand-
receptor complex through the cell in order to evoke an appropriate
response.
1. PHOSPHORYLATED PROTEINS
 Proteins are important signaling molecules. Phosphorylation at one or
more sites in a protein can alter its activity by activation or deactivation.
Typically, addition of phosphate groups in a protein takes place at a
particular site i.e. hydroxyl (-OH) groups in the side chains one of the
three amino acids;
Tyrosine
Threonine
Serine
 The transfer of the phosphate group is a reversible process. The forward
reaction (phosphorylation) is catalyzed by kinases while the backward
reaction (dephosphorylation) is catalyzed by phosphatases.
EXAMPLE
 Growth factor signaling
2. SECOND MESSENGERS
Second messengers are small, non-protein molecules that pass along a signal
initiated by the binding of a ligand (the “first messenger”) to its receptor.
I. CALCIUM IONS
 Calcium ions are a widely used type of second messenger.
 In most cells, the concentration of calcium ions in the cytosol is very low.
It is due to the normal functioning of ion-channels in the plasma
membrane.
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 The binding of a ligand to cell-surface receptors attached to the ligand-
gated calcium ion channels causes them to open and promote influx of
calcium ion. This results in increasing the intracellular levels of calcium
ions which binds to the target proteins having ion-binding sites, brings
about some conformational changes and hence, alters their activity.
EXAMPLE
 The release of insulin from β-cells of the pancreas is mediated through
high levels of intracellular calcium.
II. CYCLIC ADENOSINE MONOPHOSPHATE (cAMP)
 Cyclic adenosine monophosphate (cAMP) is a small molecule produced
by the activity of an enzyme called adenylyl cyclase. The enzyme, upon
receiving the signals, is activated and converts ATP to cAMP by removing
two phosphates and linking the last one to the sugar in a ring shape.
 One generated, cAMP activates protein kinase A that phosphorylates its
targets and passes along the signal.
EXAMPLE
 Epinephrine signaling
III. PHOSPHATIDYLINOSITOLS
 Phosphatidylinositols are phospholipids which upon phosphorylation
cleave in half and produce two secondary messengers, diacylglycerol
(DAG) and inositol triphosphate (IP3). The cleavage of the phospholipid is
catalyzed by phospholipase C that is activated in response to a signal.
 DAG stays in the plasma membrane and activates protein kinase C that
phosphorylates its target while IP3 diffuses into the cytoplasm, binds to
ligand-gated calcium channels in the endoplasmic reticulum and
increases cytosolic calcium levels that continue the signal cascade.
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MOLECULAR RECOGNITION
BINDING FORCES BETWEEN LIGANDS AND RECEPTORS
 The formation of ligand-receptor complex is promoted by chemical
bonds between functional groups on the ligand and the receptor. The
bonds formation occurs spontaneously as the ligand reaches the
appropriate distance from its receptor. The forces that bind ligands to
receptors include:
Covalent bonding
Ionic bonding
Hydrogen bonding
Charge-transfer
interactions
Hydrophobic
interactions
Dipole-dipole and ion-
dipole interactions
Van der Waals’ forces
1. COVALENT BONDING
 Covalent bond between a ligand and a receptor is formed through
sharing of electron pairs between atoms.
FEATURES
 Strongest bond that cannot be broken under biologic conditions
 Irreversible interaction between ligand and receptor
 Not occurs commonly (seldom found in drug action)
 Not desirable
EXAMPLES
 Cancer therapy
Nitrogen mustards (mechlorethamine, ifosfamide,
cyclophosphamide, chlorambucil, mustine and bendamustine) and
carboplatin bind irreversibly to DNA and cause subsequent cell
death.
 Enzyme inhibition
5-fluorouracil binds irreversibly with thymidylate synthase and
prevents generation of deoxythymidine monophosphate (dTMP)
from deoxyuridine monophosphate (dUMP).
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2. IONIC BONDING
 An ionic bond between a ligand and a receptor is formed due to
attraction oppositely charged atoms.
FEATURES
 It is most prevalent form of bonding since many of the functional groups
on the receptor and ligands are ionized at physiological pH.
 Ionic interactions are usually reversible.
 Ionic interactions are weaker than covalent.
 They are effective at distances that are considerably greater than those
required by other types of bonding.
 The strength of ionic bond decreases as the distance between the
charges increases.
EXAMPLES
 Pivagabine (anti-depressant and anxiolytic drug) binds to GABA receptor
through ionic bond formation between carboxylate residue of the drug
and amino group of the receptor.
 Acetylcholine, histamine, nicotine and adrenaline contain nitrogen atom
which are positively charged at biological pH, hence, the interaction of
these drugs with carboxylic ends of the amino acids in their receptors
(cholinergic, histamine, nicotinic and adrenergic, respectively) is through
formation of ionic bonds.
3. HYDROGEN BONDING
 It is an electrostatic interaction between the non-bonding electron pair
of a heteroatom (N, O, S) as a donor and electron deficient hydrogen
that is chemically bonded to a more electronegative atom (–SH, –NH and
–OH).
FEATURES
 Weak interaction
EXAMPLE
 Atorvastatin specifically binds to HMG-CoA reductase due to its
complementary shape and pattern of hydrogen bonding (9 specific
hydrogen bonds) and inhibits the ability of the enzyme to catalyze the
formation of mevalonate in cholesterol biosynthesis pathway.
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4. CHARGE TRANSFER INTERACTIONS
 Charge-transfer bonds are formed when an electron donor group – π-
electron rich species (alkene, alkyne, aromatic compounds) and chemical
moieties with lone pair of electrons (oxygen, nitrogen, sulfur) – transfers
a portion of its charge to the adjacent electron acceptor group.
FEATURES
 Weak interaction
EXAMPLE
 Chloroquine
5. HYDROPHOBIC INTERACTIONS
 Hydrophobic bonding occurs when non-polar sections of ligand are
closer to the non-polar sections (hydrophobic pocket) of a receptor.
FEATURES
 Very weak ligand-receptor interaction
EXAMPLE
 Lincosamides
6. ION-DIPOLE AND DIPOLE-DIPOLE INTERACTIONS
 Ion-dipole and dipole-dipole interactions take place when partial
positive or partial negative charges (due to electronegativity) form an
electrostatic bond with either partially charged atoms or ionized
elements.
FEATURES & EXAMPLE
 Weak interaction, Zaleplon
7. VAN DER WAAL’S FORCES
 A Van der Waal’s interaction between a ligand and receptor takes place
when an induced dipole in one of the participant induces dipole in the
atoms of the other participant.
FEATURES
 Very weak and temporary interaction.
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STRUCTURE ACTIVITY RELATIONSHIP
 It is the relationship between the chemical or three dimensional (3D)
structure of a molecule and its biological activity.
REASON FOR SAR STUDIES
 Discovery of lead from a compound library under investigation is the
milestone in developing clinically useful agent. A lead compound has
appropriate stereoelectronic, physicochemical, pharmacokinetic and
toxicological properties for clinical usefulness and selectivity against
chosen molecular target but suboptimal structure that requires
modifications to improve the selectivity, potency, and/or
pharmacokinetic and toxic properties.
 Hence, structure-activity relationship studies are planned to modify the
structure of a lead to produce analogues and assess the effect of these
structural changes on biological activity. These studies are performed at
lead optimization stage and are critical for identifying pharmacophore
and producing an investigational new drug with desirable properties.
STRATEGIES IN SAR STUDIES
 Every change in the chemical structure of a lead modulates its 3D,
physicochemical and biological (spectrum and potency) properties.
However, important strategies in SAR studies include;
STRUCTURAL SIMPLIFICATION (REDUCING MOLECULAR OBESITY)
 During hit-to-lead optimization, medicinal chemists always attempt to
improve the target binding affinity and maximize the in vitro potency.
This usually leads to compounds with higher molecular weights and
lipophilicities, resulting in undesirable physicochemical properties and
pharmacokinetic properties.
 For large or complex lead compounds, structural simplification is helpful
to discover drug-like molecules with improved synthetic accessibility and
favorable pharmacodynamics and pharmacokinetic profiles.
PROCESS OF REDUCING MOLECULAR OBESITY
 The typical process for structural simplification includes:
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1. Step-by-step breaking of the complex structure to generate simplified
analogues and determination of the substructures (or groups) important
for the biological activity
2. Removal of unnecessary structural motifs
3. Elimination of redundant chiral centers and rings.
EXAMPLE
 A classic example of the structural simplification of natural products is
the development of simplified morphine-derived analgesics, in which the
complex pentacyclic system of morphine was simplified step-by-step.
The pharmacophore was found to be an aromatic ring, a basic tertiary
amine and a piperidine or piperidine-mimic group.
 Compared with morphine, several simplified morphine analogues
(butophanol, pethidine and methadone) show improved potency and
reduced addiction side effects. Morphine is mainly a μ-opioid receptor
agonist, whereas pentazocine is a κ-opioid receptor agonist and μ-
receptor antagonist.
CHANGING SPATIAL STRUCTURE
 Human body presents an asymmetric environment for drug molecules to
interact with macromolecular targets (chiral nature of amino acids
imparts asymmetry to the proteins; transport, structural, receptors,
enzymes, ion channels). A drug must approach and fit closely into the
binding site of macromolecular targets to evoke the pharmacological
action, hence, must have suitable 3D shape or stereochemistry.
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 It is also well established now that the shape of a molecule is one of the
most important factors affecting the activity. Stereoisomers exhibit
different potencies, type of activity and unwanted effects. Moreover,
some enantiomers racemize endogenously and produce different
effects.
 Thalidomide developed and marketed as a racemate in 1950s for
sedation was found to teratogenic. Later, it was found that S-enantiomer
of the drug was teratogenic while R-form was sedative with non-
teratogenic potential.
CONFIGURATIONAL ISOMERS
GEOMETRIC ISOMERS
 Cis- and trans- isomers of a drug differ in their physical and chemical
properties and hence, have variable biological properties.
 Trans-isomer of diethylstilbestrol is estrogenic whereas cis-isomer has
only 7% activity. In trans-diethylstilbestrol, resonance interaction and
minimal steric interference tend to hold the two aromatic ring and
connecting ethylene carbon atom in the same plane.
OPTICAL ISOMERS
 Dextrorotatory and levorotatory isomers show similar physical and
chemical properties but differ in their interaction with plane polarized
light and biological targets.
 The binding of D(-) and L(+) ephedrine to its target shows that its D(-)
isomer has better fit and interaction with the active site of the receptor,
hence better activity than the other isomer.
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DIASTEREOMERS
 Diastereomers are the stereoisomers which are not mirror images of
eachother. They have different physical and chemical properties and
interaction with biological targets.
 Ephedrine and pseudoephedrine are diastereomers. (L)-ephedrine
shows 36 times more vasoconstrictive activity than (L)-
pseudoephedrine.
CONFORMATIONAL ISOMERS
 Conformational isomers are nonsuperimposable orientations of a
molecule which result from the free rotation of atoms about single
bonds. In order for a molecule to possess conformational isomers, it
must possess at least one single bond that is not part of a ring system.
Additionally, neither of the atoms which are joined by this single bond
can contain three identical substituents. Since almost every drug
molecule meets these criteria, conformational isomers can exist for
almost every drug. Both the number of rotatable single bonds and their
position determine whether a compound is classified as
conformationally flexible or conformationally rigid.
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ENERGETICALLY PREFERRED CONFORMER
 The conformations which minimize any repulsive interactions and
maximize all attractive interactions are more energetically favorable
than other conformations. Looking at the steric factors, the anti-
conformer of acetylcholine seems to be preferred. However, it is actually
the gauche-conformer which is preferred. The intramolecular attractive
force between the quaternary nitrogen and the ester carbonyl
overcomes steric barriers and stabilizes the gauche conformer.
ACTIVE CONFORMER
 The conformation of a drug molecule that binds to either a receptor or
an enzyme is known as its active conformation. This active conformation
contains the correct spatial arrangement of all essential binding groups
but is not necessarily the same as the most energetically preferred
conformation. While the gauche conformer of acetylcholine is
energetically preferred, the anti-conformer is required for binding to the
muscarinic receptor.
ISOSTERIC REPLACEMENTS
 Isosteres are the functional groups that have same number of atoms,
same number of total electrons and same number of valence electrons.
Groups No. of atoms No. of electrons (total) No. of valence electrons
CO2 3 6+(8*2)=22 4+(6*2)=16
N2O (nitrous oxide) 3 (7*2)+8=22 (5*2)+6=16
NO2
+
(nitrogen dioxide) 3 7+(8*2)-1=22 5+(6*2)-1=16
CNO-
(cyanate) 3 6+7+8+1=22 4+5+6+1=16
 The biological characteristics of isosteres appear to be similar; more
frequently than physical or chemical characteristics. Hence, isosteric
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replacement is often explored for the lead compound to optimize the
potency, stability and selectivity or to improve the overall ADMET
profile.
EXAMPLE
 Procainamide is a bioisostere of procaine. Both are local anesthetics,
however, procaine (containing ester group) is readily hydrolyzed in
plasma and liver by esterases. In contrast to this, procainamide
(replacement of ester group of procaine with amide) has slow hydrolysis
rate and longer duration of action.
 Aminopyrine that was marketed as analgesic and anti-inflammatory
agent was found to be carcinogenic in 1922. The isosteric modifications
of the diethyl amino group with propyl group resulted in
propylphenazone that has same degree of efficacy but is not
carcinogenic.
CHANGE PHYSICOCHEMICAL PARAMETERS
 Physicochemical properties such as degree of ionization, lipophilicity,
electronic distribution and steric effect play an important role in
determining the pharmacokinetic properties and binding-site
interactions of a lead or analogues.
DEGREE OF IONIZATION AND PKA
 For drugs, the biological potential of which result from ions, the activity
intensifies with increase in the degree of ionization. However, if the
activity results from undissociated molecules, increase in the degree of
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ionization of active compounds causes a decrease in activity. In general,
increase in ionization increases the water solubility and decreases
lipophilicity of the active compound.
 Weakly acidic drugs remain in unionized form at lower pH and are
absorbed from the stomach. Some very weak acidic drugs, such as
phenytoin and many barbiturates, whose pKa values are greater than 7,
are essentially unionized at all pH values. Therefore, for these weak
acidic drugs transport is more rapid and independent of pH.
 Most weak bases are poorly absorbed in the stomach since they are
present largely in the ionized form at low pH. Strong base, those with
pKa values between 5 and 11, shows pH dependent absorption.
LIPOPHILICITY
 Lipophilicity is a key property in transport processes, including intestinal
absorption, membrane permeability, protein binding, and distribution to
different tissues and organs, including the brain.
 An increase in the lipophilicity of a compound increases its bioavailability
due to rapid absorption through GIT membrane. However, compounds
with a log P > 5 have high metabolic turnover, low aqueous solubility
and poor distribution. In addition, highly lipophilic compounds tend to
bind to hydrophobic targets other than the desired target, and,
therefore, there is an increased risk of toxicity.
 Low lipophilicity can also negatively impact permeability and potency
and thus results in low BA and efficacy.
ELECTRONIC ENVIRONMENT
 The distribution of the electrons in a molecule has a considerable
influence on the transport and activity of a drug. In order to reach its
target a drug normally has to pass through a number of biological
membranes. As a general rule, non-polar and polar drugs in their
unionized form are usually more readily transported through
membranes than polar drugs and drugs in their ionized forms.
Furthermore, once the drug reaches its target site the distribution of
electrons in its structure will control the type of bonds it forms with that
target, which in turn affects its biological activity.
 The electronic structure of a molecule is affected by the type of
substituents and their nature (electron donating or electron
withdrawing). Hammet constant is an extensively used parameter to
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determine the effect of a particular substituent on the electronic
environment and activity of the resulting compound.
STERIC EFFECT
 For effective binding of a molecule to its target, the dimensions of the
pharmacophore must be complementary to the target site. Presence of
steric effect due to introduction of bulkier group can favor the direction
of reaction, prevent unwanted interactions and increase stability of the
resulting structure.
METHODS FOR SAR STUDIES
1. Computational methods
For predicting;
 Physicochemical properties
 Bioactivity
 Pharmacokinetics
 Pharmacodynamics (docking)
 Toxicity
 QSAR equation
2. In-vitro method
Confirming computational predictions of qualifying lead analogues
 Physicochemical properties
 Bioactivity
 Bioavailability and metabolism
 Toxicity (irritancy, embryotoxicity, cytotoxicity, hemolysis)
3. In-vivo method
Confirm the activity, pharmacokinetic changes and toxicity of
analogues in animals
APPROACHES TO SAR STUDIES
 Changing shape and size of carbon skeleton
 Changing the number of carbon in chains and rings
 Changing the degree of unsaturation
 Introducing or removing a ring system
 Changing the nature and degree of substitution
 Changing the stereochemistry
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DRUG METABOLISM
DEFINITION
“Drug metabolism or biotransformation refers to a set of chemical reactions
that are responsible for the conversion of drugs into other products
(metabolites) within the body before and after they have reached their sites of
action.”
CHARACTERISTICS
 The metabolism of a drug in the body usually occurs by more than one
route.
 The routes for metabolism of a drug normally consist of a series of
enzyme-controlled reactions. These enzymes may be specific or non-
specific. The former enzymes are stereospecific i.e. they usually catalyze
the metabolism of drugs that have structures related to those of the
normal substrates of the enzyme.
 The stereospeciﬁc nature of some enzymes means that enantiomers
may be metabolized by different routes and produce different
metabolites. Hence, racemic modiﬁcations must be treated as though
they contained two different drugs, each with its own pharmacokinetics
and pharmacodynamics.
 The ultimate end products of a drug’s metabolism are normally
pharmacologically inert compounds that are more easily excreted than
the original drug.
SIGNIFICANCE
INDICATOR OF DURATION OF ACTION OF A DRUG
 The rate of metabolism of a drug indicates the duration of action of a
drug. The drugs which are metabolized faster have short duration of
action than the one having slower metabolism.
INDICATOR OF INTENSITY OF ACTION OF A DRUG
 The rate of drug metabolism controls the intensity of the action of many
drugs by controlling the amount of the drug reaching its target site.
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DETOXIFICATION
 The metabolic routes that result in inactive metabolites are classified as
detoxification processes. For example, the detoxification of phenol
results in the formation of phenyl hydrogen sulphate, which is
pharmacologically inactive. This compound is very water soluble and so
is readily excreted through the kidney.
ACTIVATION OF A PRO-DRUG
 A prodrug – a drug delivery system containing non-toxic protective
groups used in a transient manner to alter or to eliminate undesirable
properties in the parent molecule – requires metabolism before
exhibiting its pharmacological effects.
GENERATION OF ACTIVE METABOLITES
ACTIVE METABOLITES WITH A SIMILAR ACTIVITY TO THE DRUG
 The consequence of some metabolic reactions is active metabolite/s
which can exhibit similar pharmacological effects but either a different
potency or duration of action or both with respect to the original drug.
 For example, diazepam – an anxiolytic with a sustained action – is
metabolized to the anxiolytic temazepam, which has a short duration of
action. The latter is metabolized by demethylation to the anxiolytic
oxazepam, which also has a short duration of action.
ACTIVE METABOLITES WITH A DISSIMILAR ACTIVITY TO THE DRUG
which has no relationship to that of its parent drug i.e. a different
pharmacological effect.
 For example, the antidepressant iproniazid is metabolized by
dealkylation to the anti-tubercular drug isoniazid.
ACTIVE METABOLITES WITH TOXIC EFFECTS
which either activate an alternative receptor or acts as a precursor for
other toxic compounds.
 For example, deacylation of the analgesic phenacetin yields p-
phenetidine, which is believed to act as the precursor of substances that
cause the condition methaemoglobinaemia. Phenacetin is also
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metabolized via its N-hydroxy derivative, which is believed to cause liver
damage.
CLASSIFICATION OF METABOLIC REACTIONS
PHASE I REACTIONS
 The Phase-I metabolic reactions either introduce or unmask functional
groups that act as a center for Phase II reactions.
TYPES
 The type of Phase-I reaction include
a. Oxidation
b. Reduction
c. Hydrolysis
PHASE II REACTIONS
 Phase-II reactions are conjugation reactions and involve the attachment
of a group or a molecule to the drug or metabolite.
 They may occur at any point in the metabolism of a drug or xenobiotic
but they are often the ﬁnal step in the metabolic pathway before
excretion. The products formed by these reactions are known as
conjugates. They are normally water soluble and are usually excreted in
the urine and/or bile.
 The conjugates formed are usually pharmacologically inactive although
there are some notable exceptions. For example, hepatotoxicity and
nephrotoxicity of phenacetin is due to the formation of the O-sulphate
esters.
TYPES
 Acylation
 Sulphate formation
 Conjugation with
Amino acids
Glucuronic acid
Glutathione
Mercapturic acid
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RATIONAL DRUG DESIGN
DEFINITION
“Rational drug design is an inventive process of finding new drugs based on the
knowledge of a biological target.”
NEED OF RATIONAL DRUG DESIGN
 The traditional drug design process is a non-target-based process to find
new drugs by;
1. Random screening
2. Verifying ethnopharmacological claims
3. Serendipitous method
4. Classical pharmacology
I. RANDOM SCREENING
 Screening of natural, synthetic or semi-synthetic compounds against a
number of biological assays.
II. VERIFYING ETHNOPHARMACOLOGICAL CLAIMS
 Using different biological assays to verify the traditional claims
associated with herbal drugs and identifying the active constituents
responsible for the most promising activity.
III. SERENDIPITOUS METHOD
 Accidental discovery -Finding a new activity of the compound in a library
while screening for another
IV. CLASSICAL PHARMACOLOGY
 Using cell, tissue, organ or organism-based assays to determine
compound’s activity.
 The traditional method of drug design is based on hit and trial method
and does not focus on the target, the modulation of which can produce
desirable effects.
 Therefore, it is a lengthy, nonsystematic and error-prone approach.
Moreover, it does not provide any information on the mechanisms
involved in producing the desirable outcome. In contrast to this, RDD is a
systematic approach to identify and validate a druggable target which is
used to design new drugs.
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STEPS IN RATIONAL DRUG DESIGN
1. Identify druggable target
2. Validate the druggable target
3. Design the compound library conforming to the specific requirement
4. Identify lead
5. Optimize lead
6. Pre-clinical studies
7. Clinical studies
TYPES
1. Ligand based drug design
2. Structure based drug design
3. Computer-aided drug design
4. Molecular graphics
5. Pattern recognition
6. Receptor fit
I. LIGAND BASED DRUG DESIGN
 LBDD is an approach used in the absence of the 3D information of a
biological target of interest (enzyme, receptor, ion-channel and nucleic
acid) and relies on knowledge of diverse molecules that bind to it.
II. STRUCTURE BASED DRUG DESIGN
 It is drug design approach used when the 3D information of a biological
target of interest is known.
III. COMPUTER AIDED DRUG DESIGN
 Computer-aided drug design refers to the use of computational
approaches (computing software and chemistry simulations) to discover,
develop, and analyze drugs.
IV. MOLECULAR MODELLING
 Molecular modelling is a collection of computer-based techniques for
deriving, representing and manipulating the structures and reactions of
molecules, and those properties that are dependent on these three-
dimensional structures.
V. PATTERN RECOGNITION
 PR refers to the identification or classification of patterns in large data
sets using appropriate mathematical and statistical methodologies.
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VI. RECEPTOR FIT
 It refers to pharmacological receptor characterization which involves
determining type of drug receptor interactions using instrumental
techniques such as NMR spectroscopy.
 Using the information on the type of interactions, a template
(pharmacophore) can be designed which serves as a motif to produce
library of compounds.
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COMBINATORIAL CHEMISTRY
DEFINITION
“Combinatorial chemistry involves the generation of a large array of
structurally diverse compounds through systematic, repetitive and covalent
linkage of various “building blocks”.
SIGNIFICANCE
 The combinatorial synthesis of large chemical libraries followed by high-
throughput screening is helpful in;
Rational drug designing
Speeding-up the process of drug discovery and development
Efficient screening and testing of combinatorial library
Lowering the cost associated with the research and development
LINKING COMPUTATIONAL CHEMISTRY WITH COMBINATORIAL
CHEMISTRY
 With increase in understanding and maturation of fields of
combinatorial chemistry and computational chemistry, it is clear now
that combining the two can lead to higher hit and lower attrition rates.
 It is more cost-effective to design and screen virtual chemical libraries in
silico prior to the actual synthesis and screening of the libraries.
Computer-assisted drug design, such as generation of virtual libraries,
analogue docking and in silico screening are hence the standard
procedure in rational drug discovery programs.
GENERATING COMBINATORIAL LIBRARIES
Methods of generating
combiantorial libraries
Solid-phase synthesis
Solution-phase
synthesis
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1. SOLID-PHASE SYNTHESIS
 Solid phase synthesis is heterogeneous reaction in which target
molecules are synthesized in well-ordered sets (arrays) from a building
block attached to a solid support.
PRINCIPLE
 A building block containing reactive functional groups is coupled to a
solid support via chemical functionality. A multistep synthesis transforms
the bound building block into the target molecule which is eventually
cleaved from the support.
REQUIREMENTS FOR SOLID-PHASE SYNTHESIS
 Solid support
 Anchor (Linker and Spacer)
 Protection group
 Cleavage reagents
I. SOLID SUPPORT
 A solid support refers to cross-linked, insoluble and solvent swellable
polymeric molecules that are inert to the condition of synthesis.
PROPERTIES
 Solvent swellable
 Insoluble
 Stable to reaction conditions
EXAMPLES
 Polystyrene resin
 Polyamide resin
 Cellulose
 Coated glass and ceramic beads, pins and microchip
II. ANCHOR
 An anchor is a resin-immobilized functional group forming a cleavable
coupling site.
LINKER
 Linkers are bifunctional molecules that anchor building block to the solid
support.
 PROPERTIES
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Irreversibly attached to solid support
Easily cleavable using mild conditions without damaging final
product
Stable to reaction conditions
Regenerate the originally linked functionality
 EXAMPLES
Carboxylic acid linker
Carboxamide linker
Alcohol linker
SPACER
 It is a functional moiety between solid support and linker.
 PROPERTIES
Reduces steric hindrance
Remains with solid support after cleavage
III. PROTECTION GROUPS
 They are the functional groups that are used to protect at all reactive
sites in the building blocks.
 The order of deprotection ensures that the reaction proceed in a
desirable manner i.e. intended reactions take place at a particular
reactive site.
IV. CLEAVAGE REAGENTS
 Acids
 Bases
 Enzymes
 Electromagnetic radiation
 Oxidizing and reducing agents
 Palladium
METHODOLOGY
 Solid phase synthesis is heterogeneous reaction in which a building block
is coupled to a solid support via chemical functionality present on solid
support.
 A multistep synthesis transforms the bound building block into the
target molecule which is eventually cleaved from the support.
APPLICATIONS
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 Synthesis of peptides, deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA)
 Synthesis of benzodiazepines
 Synthesis of benzopyran derivatives
 Synthesis of (±)-epibatidine
ADVANTAGES
 Ease of isolation (usually by filtration)
 Removal of unreacted reagents is possible so large excesses can be used
to drive the reaction to completion
2. SOLUTION-PHASE SYNTHESIS
 Solution-phase synthesis involves conducting chemical reaction
simultaneously in well-ordered sets (arrays) of reaction vessels in
solution.
PRINCIPLE
 Compound libraries are formed by reacting each of members of a one
set of similar compounds with the each of members of the second set of
compounds. The reaction vessel contains building blocks dissolved in a
solvent or attached to a soluble support.
TYPES
SOLUTION PHASE SYNTHESIS WITHOUT USING SUPPORTS
 Parallel synthesis of aminothiazoles (Single vessel single product)
 Synthesis of amides (Libraries of mixtures)
SOLUTION PHASE SYNTHESIS USING POLYETHYLENE GLYCOLS AS SOLUBLE
SUPPORTS
 PEG contains hydroxy groups at each end of the chain. Combinatorial
syntheses in solution can be carried out using monomethyl polyethylene
glycol which precipitates in diethyl ether.
ADVANTAGES
 Synthesis may be possible by linear and convergent approach.
 Unmodified traditional organic reactions may be used
 Does not require additional synthesis steps to attach the initial building
block to and remove the product from the support.
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 Final product is not likely to be contaminated with truncated
intermediates.
 Easy characterization
APPLICATIONS
 Synthesis of peptides
 Synthesis of substituted benzoxazinones
 Synthesis of thiohydantoine
PURIFICATION TECHNIQUES
 Liquid-liquid extraction (especially for solution-phase synthesis)
 Solid-phase extraction (filtration and adsorption to a suitable surface)
 Fluorous phase extraction (attachment of an insoluble perfluorinated
moiety with the compound and retain the molecule from fluorous
solvent)
LIBRARY FORMATS
 One bead one compound library
 Pre-encoded libraries
 Spatially-addressable libraries
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COMPUTER AIDED DRUG DESIGN
DEFINITION
“Computer-aided drug design refers to the use of computational approaches
(computing software and chemistry simulations) to discover, develop, and
analyze drugs and similar biologically active molecules.”
SIGNIFICANCE
 The drug discovery and development of novel bioactive compounds is a
complex and lengthy process. It is evident from the reports that in the
United States, a new chemical entity requires 10-15 years of research
and costs more than $300 million before entering in the market.
 Despite the technological advancements in target identification,
chemical synthesis and screening methods which have made the drug
development process relatively fast, it is a tragic truth that a vast
majority of compounds (99.99%) never become a drug. The contributing
factors to high attrition rate at different stages of drug discovery include;
Low bioavailability
Poor pharmacokinetics
High toxicity
Drug drug interactions
 However, computational prioritization before in-vitro and in-vivo
experimentation can ensure that only valuable resources are
apportioned to the most promising candidates.
 The computational tools are helpful in;
Rational drug designing
Speeding-up the process of drug discovery and development
Efficient screening and testing of compound library
Removing hopeless candidates in early stages and reducing high
attrition rates in later stages of drug development
Lowering the cost associated with the research and development
APPLICATIONS
 The computational programs may be used at any of the following stages
of drug discovery;
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TARGET IDENTIFICATION
 Bioinformatics
 Reverse docking
 Prediction of protein structure
 Predicting bioactivity of compound library
TARGET VALIDATION
 Prediction of druggability of the chosen target
 Designing of tool compounds
LEAD DISCOVERY
 De-novo drug design
 Designing compound library
 Determination of drug-likeliness parameters of compound library
 Identification of pharmacophore
 Determination of flexibility of target
 Molecular docking (scoring)
 Determination of ligand-binding site interactions
LEAD OPTIMIZATION
 Quantitative structure activity relationship
 3D- Quantitative structure activity relationship
 Structure-based optimization
PRE-CLINICAL STUDIES
 In-silico ADMET prediction
 Physiologically-based pharmacokinetic simulations
 In-vitro/in-vivo correlation studies
TYPES
 Ligand Based Design
 Structure Based Design
SUCCESS STORIES OF CADD
STRUCTURE-BASED DRUG DESIGN
 Potassium channel blocker (sotalol; anti-arrhythmic drug)
CHEMICAL DESCRIPTOR BASED DRUG DISCOVERY
 Calcium channel antagonist (amlodipine; anti-hypertensive)
DE-NOVO DESIGN + DOCKING
 Thrombin inhibitor (hirudin; anti-coagulant)
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SOFTWARES FOR CADD
Databases
 Zinc Database,
 ChEMBL
 Jchem for Excel
 Protein Data Bank (PDB)
 STITCH
Sketch or drawing tools
 ChemDraw
 MarvinSketch
 ChemWriter
 Pymol
 ChemSketch
Molecular modeling
 SwissParam
 SwissSideChain
Homology modeling
 SWISS-MODEL
 SWISS-MODEL Repository
Binding cavity prediction
 FINDSITE
 3DLigandsite
 COACH
Docking
 AutoDock
 1-Click Docking
 SwissDock
Target prediction
 SwissTargetPrediction
 ChemPort
QSAR
 clogP
 cQSAR
 ChemDB
ADME
 SwissADME
 PROTOX
 ADMET
Binding free energy
 NNScore
 BAPPLServer
Software
for
CADD
Databases
Sketch or draw tools
Molecular modeling
Docking
QSAR
ADME
Binding free energy
determination tool
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ANTISENSE MOLECULES
INTRODUCTION
 Antisense therapy is a form of treatment for genetic disorders or
infections. When the genetic sequence of a particular gene is known to
be causative of a particular disease, it is possible to synthesize a strand
of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the
messenger RNA (mRNA) produced by that gene and inactivate it,
effectively turning that gene "off". This is because mRNA has to be single
stranded for it to be translated.
PRINCIPLE OF THERAPY
 Most human diseases are caused by production of abnormal or
malfunctioning proteins. Antisense therapy involves inhibiting
production of these proteins. The antisense oligonucleotide binds to
mRNA and inhibits protein synthesis by two mechanisms;
Stopping the ribosome from reading the sequence
Destroying target mRNA by recruiting the enzyme “RNase”
ADVANTAGES
 Effects of antisense therapy are similar as of enzyme inhibitor and
receptor antagonist, however, smaller doses are needed that is why side
effects are also less. Antisense therapy also imparts specificity to the
treatment.
DISADVANTAGES
 Short lifetime
 Poor absorption
 Instability of oligonucleotides
 Difficulty in expressing RNA only in targeted tissue
EXAMPLE
 Mipomersen for homozygous familial hypercholesterolemia (mutations
in LDL-R gene that encodes LDL receptor protein)
 Formi virsen for cytomegalovirus retinitis (inflammation of retina caused
by CMV that leads to blindness) in AIDS patients.
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Chapter 2 – Drug Target and Drug Designing
GM Hamad
DRUG TARGETS
DEFINITION
 A drug/druggable target is a naturally existing cellular/molecular
structure involved in pathogenesis, the direct or indirect inhibition or
activation of which will elicit a measurable biological response.
CLASSES OF DRUG TARGETS
 Following are the drug targets:
Enzymes
Receptors
Proteins
Membrane lipids
Carbohydrates
Nucleic acids
Ion channels
1. ENZYMES
 Enzymes are organic, thermolabile catalysts produced by the living
organisms. They increase the rate of a chemical reaction without any
permanent change in their structure or being consumed in
the process.
 Almost all chemical reactions in the body are catalyzed by enzymes.
During their catalytic activity, enzymes;
Hold substrate in the active site in such a position that it can easily
and effectively be attacked by the reagent
Provide functional groups that will attack the substrate and carry
out the biochemical reactions
 Enzymes generally make good drug targets because a specific reaction of
interest can be targeted with a high degree of selectivity.
 Drugs acting on enzymes can either increase or decrease the rate of
reactions mediated by them. Hence, are classified as;
Enzyme activators
Enzyme inhibitors
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2. RECEPTORS
 Receptors are macromolecules that specifically recognize and bind a
ligand and, transduce and integrate the signal received from it into
biological systems.
CLASSES OF RECEPTORS
 Cell surface receptors
G protein coupled receptors
Ion channel linked receptors
Enzyme linked receptors
3. CELL MEMBRANE LIPIDS
 Drugs can interact with membrane lipids and disrupt the function of cell
membrane by interfering with its permeability.
EXAMPLE
 Anesthetics
 Anti-fungal agents (Amphotericin B)
 Gramicidin and Megainins (peptide antibiotic)
 Valinomycin
4. CARBOHYDRATES
 Carbohydrates play an important role in cell recognition, regulation and
growth. They are important targets for treatment of viral and bacterial
infections, cancer and auto-immune diseases. They also act as antigens.
EXAMPLE
 Antibodies recognize the antigen on the foreign cells and mark it for
destruction. Then, immune system destroys the cell. Hence, act as anti-
cancer agents.
5. NUCLEIC ACIDS
Nucleic acids are biopolymers composed of nucleotides i.e. monomers made of
three components: a 5-carbon sugar, a phosphate group and a nitrogenous
base.
DRUGS ACTING ON DNA
 Intercalating agents
 Alkylating agents
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 Chain cutters
DRUGS ACTING ON RNA
 Antibiotics
 Antisense molecules
DRUGS ACTING ON NUCLEIC ACID BUILDING BLOCK
 Antiviral agents
6. ION CHANNELS
 Ion channels are pore-forming membrane proteins whose functions
include establishing a resting membrane potential, shaping action
potentials and other electrical signals by gating the flow of ions across
the cell membrane, controlling the flow of ions across secretory and
epithelial cells, and regulating cell volume
TYPES
 Voltage gated ion channels
 Ligand gated ion channels
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DRUG DISCOVERY AND DEVELOPMENT
INTRODUCTION
 Discovery and development of new natural and synthetic compounds
comes under the umbrella of medicinal chemistry research.
 The discipline encompasses background knowledge and understanding
of physicochemical properties of compounds to produce novel agents,
elucidation of mechanisms of action and correlation of the structure
with biological activity, molecular docking, and pharmacokinetics,
metabolomics and toxicological profiling to select the most promising
candidates for treatment of a disease condition.
DRUG DISCOVERY
 Drug discovery is a systematic approach which involves setting up of a
working hypothesis of the target for a particular disease, establishing
suitable models for estimation of biological activities and screening of
large libraries of molecules to identify lead compounds.
DRUG DEVELOPMENT
 Drug development takes into account the pre-clinical and clinical studies
on the most promising candidate and its regulatory approval.
DRIVING FORCES FOR THE DRUG DISCOVERY AND DEVELOPMENT
PROGRAMS
 The novel comprehensions into a disease process or targeting
technologies and unsatisfied clinical needs are the driving forces for the
drug discovery programmes.
 The general steps towards discovery of innovative leads are as follows:
STEP 1: IDENTIFICATION AND SELECTION OF A “DRUGGABLE TARGET”
 A druggable target is a naturally existing cellular/molecular structure
involved in pathogenesis, the direct or indirect inhibition or activation of
which will elicit a measurable biological response.
 The major classes of the drug targets are enzymes (proteases, estrases,
phosphatases and protein kinases), proteins (structural or transport),
receptors (nuclear hormone and G-protein coupled), nucleic acids and
ion-channels (ligand-gated and voltage-gated).
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 These targets may be a newly discovered or explored protein or the ones
with sound scientific understanding on their function in both
physiological and pathological conditions. The process of the selection
and prioritization of a diseased target can be made efficient through
mining of the data from gene expression, proteomics, transgenic
phenotype profile, patents and publications.
STEP 2: TARGET VALIDATION
 Target validation is an approach to verify that a molecular target is
directly involved in a disease process, and that modulation of the target
is likely to have a therapeutic effect.
 Most powerful target validation tools include monoclonal antibodies and
transgenic animals and chemical genomics.
STEP 3: LEAD DISCOVERY
 A “lead” refers to a compound having sufficient potency, efficacy and
selectivity for the chosen target, and favorable drug-like features but
suboptimal structure requiring modifications to enhance the ligand-
binding site interactions.
 The process of lead discovery consists of various steps that are
summarized as follows:
STEP 3.1. DEVELOPMENT OF SCREENING PROGRAMS
 The first step in lead discovery is the development of programs for
screening the compounds at the validated target. These programs may
include high-throughput screen (HTS), focused screen, fragment screen,
physiological screen and virtual screen (VS).
 Amongst all, HTS and VS (analysis of library compounds using in vitro
assays in microtiter plate and molecular docking, respectively) are the
most commonly used screening programs. However, high cost and low
hit rate associated with the former call for the use of later method to
filter large chemical libraries into manageable ones.
STEP 3.2. GENERATION OF “HIT” SERIES
 A “hit” series refers to the library of compounds showing sufficient
selectivity and potency against the chosen target during the screening
programs that can be confirmed upon retesting.
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STEP 3.3. COMPUTATIONAL PRIORITIZATION OF THE DRUG-LIKE
COMPOUNDS FROM “HIT” SERIES
 In the initial stages of lead discovery, it is imperative to select the small
and simple molecules since in the optimization phase, structural
modifications to improve potency and selectivity result in increasing the
molecular weight which in turn creates safety and tolerability issues.
 The recent advances in the computational chemistry enable the
researchers to scrutinize the hits into leads based on several
physiochemical, pharmacokinetic and toxic properties. A compound is
deemed to be drug or lead like if it passes through filters such as Lipinski
Rule of Five, Rule of Three, Veber Rules, CMC-50 Like Rules, BBB Rules,
MDDR Rules and Ghose Filters.
 The most commonly observed parameters in such cases include
molecular weight, hydrogen bond donors and acceptors, rotatable
bonds, polar surface area, molar refractivity, number of atoms and rings,
and log P.
Step 3.4. Generation of dose-response curves of the successful lead
candidates through primary and secondary biological assays
 The dose-response curves generated through primary biological assays
on isolated or engineered protein provide information on competitive
behavior of hits for the target. Compounds showing an “all or none”
response at low concentrations are believed to have no binding to the
target while those having irreversible interactions are rejected also. The
compounds with reversible biding are considered since their effects can
be “washed-out” following the withdrawal.
 The secondary biological assays are carried out on cells, tissues or
whole-animals, predictive of a particular disease state, in order to
evaluate efficacy and safety. Furthermore, the data obtained reassure
that the successful compounds can modulate intact systems rather than
the isolated simple proteins.
 The net result of the dose-response curves is the data on “half maximal
inhibitory concentration” that can be used for comparison of the
potencies of the lead candidates with the standards.
STEP 3.5. PHARMACOKINETICS STUDIES
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 This stage involves detailed in vitro validation of the computationally
determined physicochemical and pharmacokinetic properties including
lipophilicity, aqueous solubility, log S and log D (solubility and
permeability as a function of pH, respectively), Caco-2 and MDR1-MDCK
permeability, and microsomal stability.
 These parameters help in selection of the lead candidates having
optimal pharmacokinetics to be subjected to in vivo experimentation for
obtaining data on bioavailability, distribution, metabolism, half-life,
clearance and interactions with food or metabolic enzymes.
STEP 3.6. TOXICITY STUDIES
 In pre-clinical toxicity studies, the lead candidates are subjected to
various in vitro (cytotoxicity, genotoxicity, mutagenicity and lethality)
and in vivo (developmental toxicity, acute oral toxicity and repeated-
dose toxicity) assays.
 The doses are usually selected based on the data from the
pharmacological experimentation.
STEP 3.7. STRUCTURE-ACTIVITY RELATIONSHIP (SAR)
 The last step in lead discovery is an intensive and systematic SAR studies.
Each and every part of structure of the successful lead candidate is
considered and effect of removal or introduction of a particular group on
the magnitude of activity and selectivity are measured.
STEP 4: LEAD OPTIMIZATION
 Lead optimization, the final stage in drug discovery, aims to improve the
deficiencies and modify the properties of the lead compound by taking
into account the SAR and chemical stability data. The end result of the
process, the optimized lead (drug candidate) then makes its way to the
pre-clinical and clinical development.
 The pre-clinical development provides comprehensive information on
the dosing and safety of the drug candidate in animals. Most of the
organizations start the Investigational New Drug (IND) Process before
conducting the clinical trials and ask for the guidance and assistance
from Food and Drug Administration. The process of generating and
gathering data on humans continues until a marketing application is filed
and upon approval the “new drug” finds its place in market.
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 Note: It is noteworthy that only 10% of the molecules under
consideration in drug discovery program pass to the pre-clinical and
clinical phase.
 The major attributable factors for such high attrition rate include;
Inability to develop reliable screening assays
No developable hits identified by screening
Variable behavior of the hits in biological assays
Poor pharmacokinetic or pharmacodynamics profile
Side effects that cannot be separated from the mechanism of
action of the target
In vitro and in vivo toxicity
 However, the process of drug discovery does not cease and the working
on the backup series is continued to prevent failure of the program.
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STRUCTURE BASED DESIGNING
DEFINITION
 It is drug design approach used when the 3D information of a biological
target of interest is known.
INTRODUCTION
 The 3D structure of various biological targets can be obtained from
protein data bank (PDB). However, when the target is newly discovered,
its structure can be determined by using;
Instrumental techniques (x-ray crystallography and protein
nuclear magnetic resonance spectroscopy)
Homology approach (constructing an atomic resolution model of
the target based on experimental structure of related homologous
protein)
 Using the structure of the biological target, candidate drugs that are
predicted to bind with high affinity and selectivity to the target may be
designed using interactive graphics, intelligence of a medicinal chemist
and automated computational procedures.
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APPLICATIONS
STRUCTURE-BASED VIRTUAL SCREENING
IDENTIFICATION OF BINDING SITE
 SBDD is used for identification of concave surfaces on the target that can
accommodate drug sized molecules that also possess appropriate "hot
spots" (hydrophobic surfaces, hydrogen bonding sites, etc.) that drive
ligand binding.
DETERMINATION OF BINDING AFFINITY
 SBDD is used for determination of the strength of binding of ligand at
the binding site of the target.
DETERMINATION OF BINDING CONFORMATION
 SBDD is used for determination of conformation (pose) of ligand relative
to the best binding affinity scores.
DETERMINATION OF LIGAND-BINDING SITE INTERACTIONS
 SBDD is used for determination of chemical bonds (type and strength)
formed between functional groups of ligand and amino acid residues of
the target for molecular recognition.
DE-NOVO DESIGN OF NOVEL LIGANDS
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 Using the 3D information of the target’s structure, ligand molecules are
built up within the constraints of the binding pocket by assembling small
pieces in a stepwise manner. These pieces can be either individual atoms
or molecular fragments.
LEAD OPTIMIZATION
 SBDD is used for optimization of lead compounds by evaluating
proposed analogs within the binding cavity.
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LIGAND BASED DESIGNING
 Indirect drug design
DEFINITION
 LBDD is an approach used in the absence of the 3D information of a
biological target of interest (enzyme, receptor, ion-channel and nucleic
acid) and relies on knowledge of diverse molecules that bind to it.
APPLICATIONS
DESIGNING PHARMACOPHORE MODEL
 The information obtained from binding of different molecules with the
biological target of interest can be used to obtain a pharmacophore
model that defines the minimum necessary structural characteristics a
molecule should have so as to bind to the target. Then, a series of novel
compounds sharing similar structural skeleton can be developed.
ENGINEERING BIOLOGICAL TARGET MODEL
 A model of the biological target can be engineered based on the
information of what binds thereto, and this model consecutively can be
accustomed to design new molecular entities that interact with the
target.
QSAR STUDIES
 In LBDD, a quantitative structure-activity relationship (QSAR) devised
already between calculated properties of a series of similar molecules
and their experimentally determined biological activity can be used to
predict the activity of latest analogs.
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DRUG SYNTHESIS
INTRODUCTION
 The word synthesis refers to “man-made”. Chemical synthesis is a
process in which one or more reactants react to form one or more
products.
NEED OF CHEMICAL SYNTHESIS
 The process of chemical synthesis is aimed at the generating such
compounds that have therapeutic or commercial advantage over the
existing ones.
GENERAL CONSIDERATION BEFORE CHEMICAL SYNTHESIS
 The process of chemical synthesis is usually laborious and requires
comprehensive knowledge of basic principles of organic and inorganic
chemistry for the successful outcome. Therefore, before starting a
synthesis process, due consideration must be given to the following;
STARTING MATERIAL
 The choice of starting materials is important in any synthetic route.
Common sense dictates that they should be chosen on the basis of;
What will give the best chance of reaching the desired product
Cost
Availability
Reactant’s exposure-associated risks and hazards
CHEMICAL REACTION
 The chemical reactions selected for the proposed synthetic pathway will
obviously depend on the structure of the target compound. However, a
number of general considerations need to be borne in mind when
selecting these reactions includes:
The yields of reactions should be high, particularly when the
synthetic pathway involves a large number of steps.
The products should be relatively easy to isolate, purify and
identify.
Reactions should be stereospeciﬁc.
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The reactions used should be adaptable to large-scale production
methods.
DESIGN OF PATHWAY/ROUTE OF SYNTHESIS
 The design of pathway for synthesis of target compounds depends on;
Chemistry of functional groups
Carbon skeletons associated to functional groups
 Ideally, the chosen route should be;
Easy to modify the structure of the lead compound either directly
or during the course of its synthesis.
Economic (less number of steps and reactants)
Diverse (produce a greater range of analogues)
Including stages where it is possible to introduce new side chains
and substituents
PROTECTION STRATEGY
 The design of synthetic pathways often requires a reaction to be carried
out at one center in a molecule, the primary process, whilst preventing a
second center from either interfering with the primary process or
undergoing a similar unwanted reaction. This objective may be achieved
by careful choice of reagents and reaction conditions or combining the
second center with a protecting group. Whenever, protection strategy is
used, following must be considered;
The protection group must be easy to attach to the relevant
functional group
The protected site should form a stable structure that is not
affected by the reaction conditions and reagents being used to
carry out the reaction
The protection group should be easily removed once it is no
longer required
In some circumstances, protecting groups may not be removed
but converted into another structure as part of the synthesis
CLASSIFICATION
BASED UPON THE NUMBER OF STEPS INVOLVED IN THE CHEMICAL REACTION
I. ELEMENTARY REACTIONS
 A chemical reaction that takes place in one step to produce target
molecule is called elementary reaction.
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 Based upon the number of molecules taking part, elementary reactions
can be uni-molecular, bimolecular and ter-molecular reactions having
one, two, and three molecules as reactants, respectively.
II. COMPLEX REACTIONS
 A chemical reaction that takes place in multiple steps to produce target
molecule is called complex reaction. In such reactions, one product of a
reaction is treated with another reactant to form another product and
this is continuously done until target compound is reached.
BASED ON STRATEGY OF SYNTHESIS
I. GROUP ORIENTED SYNTHESIS
 It involves interconversion, addition, removal, masking or unmasking of
functional group/s.
II. BOND ORIENTED SYNTHESIS
 It involves formation or breaking of bonds or fusion of one ring with
another ring or a chemical moiety.
III. RETROSYNTHESIS
 It is the reverse of a synthetic reaction. This approach starts with the target structure
and then works backwards by artiﬁcially cutting the target into sections known as
synthons. Each of the possible synthons is converted on paper into a real compound
known as a reagent whose structure is similar to that of the synthon. The
disconnection selected for a step in the pathway is the one that gives rise to the best
reagents for a reconnection reaction.
IV. CONSTRUCTION MOTIFS
 It involves use of available natural or synthetic compounds containing
the main part of the target structure and modifying their structure to
produce the desired product.
BASED ON ROUTE OF SYNTHESIS
I. LINEAR
 In linear route of synthesis, one step in the pathway is immediately
followed by another until target compound is reached.
II. CONVERGENT
 In convergent route of synthesis, two or more sections of the molecule
are synthesized separately before being combined to form the target
structure.
III. DIVERGENT
 In a divergent synthesis, several compounds are prepared from a
common intermediate.
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BASED ON SYNTHETIC PATHWAY
FULL SYNTHETIC PATHWAY
 Full synthetic pathway involves the use of traditional organic synthesis
to convert the reactant to the target structure.
PARTIAL SYNTHETIC PATHWAY
 Partial synthetic pathways use biochemical and other methods to
produce the initial starting materials and traditional organic synthesis to
convert these compounds to the target structure.
ASYMMETRY IN SYNTHESIS
 The presence of an asymmetric center or centers in a target structure
requires;
USE OF NON-STEREOSELECTIVE REACTIONS TO PRODUCE STEREOSPECIFIC
CENTRES
 Non-stereoselective reactions produce either a mixture of
diastereoisomers or a racemic modiﬁcation. In such instances, isolation
and purification of desirable product is needed which can considerably
reduce the overall yield.
 Diastereoisomers exhibit different physical properties. Consequently,
techniques utilizing these differences may be used to separate the
isomers. The most common methods of separation are fractional
crystallization and appropriate forms of chromatography.
 The separation (resolution) of a racemic modiﬁcation into its constituent
enantiomers is normally achieved by converting the enantiomers in the
racemate into a pair of diastereoisomers by reaction with a pure
enantiomer. Enantiomers of acids are used for racemates of bases whilst
enantiomers of bases are used for racemates of acids.
USE OF STEREOSELECTIVE REACTIONS TO PRODUCE STEREOSPECIFC CENTRES
 Stereoselective reactions result in the selective production of one of the
stereoisomers of the product.
 The stereoselectivity in synthesis can be achieved by using;
Catalyst (enzymatic or non-enzymatic)
Chiral agents (building blocks and auxiliary)
Achiral reactants and substrate
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Chapter 3.1 – Hormones
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HORMONES
DEFINITTION
“Hormones are chemical messengers needed in small concentrations to
inhibit or accelerate the metabolic activity of the target organ.”
OR
“A hormone is a class of signaling molecules produced by glands in
multicellular organisms that are transported by the circulatory system to
target distant organs to regulate physiology and behavior.”
OR
“Hormones are substances produced by highly specialized tissues called the
"Endocrine" or "ductless glands", carried by the blood stream to target
organs for exerting characteristic physiological effects.”
CHEMICAL CLASSIFICATION OF HORMONES
1. PROTEIN / PROTEIN DERIVATIVES (POLYPEPTIDE)
 Protein derivatives contain hormone secreted by anterior and
posterior pituitary gland and pancreas. E.g, insulin, glucagon
2. STEROIDAL HORMONES
 Hormones secreted by ovaries, testes and adrenal cortex. E.g,
corticosteroids, estrogen, progesterone, testosterone.
3. AMINO ACIDS
 Hormones secreted by thyroid and adrenal medulla. E.g, thyroidal
hormones.
RELATED COMPOUNDS
 Following are the compounds related to hormones:
Vitamins
Enzymes
COMPARISON BETWEEN HORMONES, VITAMINS AND ENZYMES
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CHARACTER HORMONE ENZYME VITAMINS
DEFINITION
Molecules (peptide /
steroid) that triggers
specific cellular
reaction in target
tissues and organs at
some distance away
Biological
macromolecules which
speed up the chemical
reactions without
undergoing any change
Essential micro-
nutrients needed for
proper functioning of
metabolism
CHEMICALLY
Glycoprotein, steroid
or polypeptide
Always proteinaceous
in nature
Organic acid / amide /
amine / ester / alcohol
or steroid
OCCURANCE
Internal supplies
secreted in our body
Internal supplies
present within our
body
External supplies
obtained from food
PRODUCED
BY
Endocrine gland Exocrine gland Taken by food
DEFICIENCY Hormonal disorder
Required in small
amount
Disease
EXAMPLE
Melatonin, insulin,
thyroid hormone
Protease, amylase,
lipase, transferase
Vitamin A, D, E, K, B, C
1. STEROIDAL HORMONES
DEFINITION
“Any compound containing steroidal ring is called steroid / steroidal
hormone.”
 Steroids forms a group of structurally related compounds, which are
widely distributed in animal and plant kingdom. The structure of steroids
are based on the 1,2 Cyclopentanophenanthrene skeleton.
THERAPEUTIC USES OF STEROIDAL HORMONES
 Steroids or steroid hormones are naturally occurring compounds which
are responsible for maintaining, development and regulation of
reproductive system.
 These drugs are used primarily in;
Birth control
Hormone-replacement therapy (HRT)
Inflammatory conditions
Cancer treatment
CHEMISTRY OF STEROIDAL HORMONES
 The steroidal hormones are chemically based on a common structural
backbone, the steroid backbone.
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 Although, steroidal drugs share a common structural foundation, the
variations in the structures provide specificity for the unique molecular
targets.
BIOSYNTHESIS OF STEROIDAL HORMONES
 Steroid hormones in mammals are biosynthesized from cholesterol,
which in turn is made in vivo from acetyl-CoA via the mevalonate
pathway.
 The biosynthetic pathways for steroidal hormone (Testosterone,
Progesterone, Estrogen, Aldosterone, Cortisol) are as follows;
CONVERSION OF CHOLESTEROL TO PREGNENOLONE
 It is the rate-limiting step in steroid hormone biosynthesis due to the
dependency of cholesterol on Steroidogenic Acute Regulatory protein to
translocate it to the inner mitochondrial membrane of steroid-
synthesizing cells.
 P450scc mediates the cleavage of the C-17 side chain on the D ring of
the sterol to provide pregnenolone. Pregnenolone can be either directly
converted into progesterone or modified for synthesis of GCs, estrogens,
and androgens.
ROUTE 1: PROGESTERONE AND ALDOSTERONE PATHWAY
 Conversion of pregnenolone to progesterone.
This transformation is mediated by a bifunctional enzyme,
hydroxysteroid dehydrogenase (HSD) that causes oxidation of the
alcohol at C-3 to ketone and isomerization of double bond at 5-6C
to 4-5C to produce progesterone.
 Conversion of progesterone to aldosterone
Progesterone is directly acted on by 21-hydroxylase and
aldosterone synthase (a multifunctional enzyme, mediates the
hydroxylation at C11, as well as the two-step oxidation of C18 to
an aldehyde) providing aldosterone
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ROUTE 2: SEX STEROID HORMONES AND GLUCOCORTICOIDS PATHWAY
 Conversion of pregnenolone to 17-hydroxy pregnenolone
Hydroxylation at C17 produces 17-hydroxy pregnenolone
 Conversion of 17-hydroxy pregnenolone to cortisol
Hydroxylation at C11 and HSD activity at 3C produces cortisol
 Conversion of 17-hydroxy pregnenolone to androgens and estrogens
The lyase oxidatively removes the two carbons at C17, providing
the C17 ketone which in the case of 17-hydroxypregnenolone is
dehydroepiandrosterone (DHEA). DHEA is converted to
androstenedione by the action 3-HSD. If 17-hydroxyprogesterone
is the substrate, androstenedione is resulted.
 Androstenedione can either be converted to;
Testosterone (due to 17-HSD) which in turn is aromatized to
estradiol by aromatase.
Estrone by aromatase.
NOTE
 Cholesterol is the precursor of all sex hormones.
 In direct route, only progesterone is formed directly from cholesterol
while estrogen and testosterone are formed indirectly from
progesterone.
 Testosterone is the precursor of estrogen hormone.
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CLASSIFICATION OF STEROIDAL HORMONES
 Classes of steroidal hormones are;
Testosterone
Progesterone
Estrogen
Aldosterone
Cortisol
I. TESTOSTERONE
INTRODUCTION
 Testosterone is the male sex hormone which is responsible for the
development, maintenance, and regulation of the male reproductive
system and secondary sex characters of male.
 It belongs to the class of androgens. The androgens are a group of
steroids that have anabolic and/or masculinizing effects in both males
and females.
 The site of action of testosterone is androgen receptor.
MECHANISIM OF ACTION
 Testosterone antagonizes the androgen receptor to induce gene
expression that causes the growth and development of masculine sex
organs and secondary sexual characteristics.
THERAPEUTIC USES
 Testosterone controls the development as well as maintenance of male
sex organs and is solely responsible for the male secondary sex
characteristics.
 It also increases the size of scrotum, phallus, seminal vesicles, prostate
and enhance the sexual activity of adolescent males.
 Androgen replacement therapy in men having hypogonadism.
 Treatment of breast cancer in post-menopausal women.
BIOSYNTHESIS
 Biosynthesis is given earlier (Biosynthesis of Steroidal Hormone).
MEDICINAL CHEMISTRY
 It contains a steroidal ring. It consists of 4 fused rings A, B, C, D
A = cyclohexanone
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B = Cyclohexane
C = Cyclohexane
D = Cyclopentane
 They are important androgens. They possess androgenic and anabolic
activity (growth of new cells). Introduction of methyl group at carbon 17
along with hydroxyl, leads to formation of methyl testosterone. It can be
given orally. Methyl group is responsible for metabolic process. While
oxygen of hydroxyl group is responsible for receptor binding.
 Keto group at carbon 3 is responsible for androgenicity not for
anabolicity.
 Introduction of halogen at any position will lead to decrease of activity
except position no. 4 and 9 of steroidal nucleus. The activity is enhanced
when halogen is introduced at C-4 or 9. For e.g. floxymetreone is
obtained after the attachment of fluorine at C-9. It is 5 times more
potent than methyl testosterone.
 The androgenic and anabolic, both activities are decreased when
testosterone is reduced into dihydrotestosterone.
 First and second ring is in Trans-configuration form, if converted into Cis-
configuration the activity will be lost.
ASSAY
 Dilute the sample in alcohol to 50ml with ethyl alcohol. Measure the
absorption at 241nm.
BRANDS
 Sustanol – Pharmatec Pakistan
 Testoviran – Bayer Healthcare
 Syandrol – Pfizer
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II. PROGESTERONE
INTRODUCTION
 Progesterone is a female sex hormone which is responsible for the
development, maintenance, and regulation of the female reproductive
system and secondary sex characters of female.
 Progesterone belongs to the class of Estrogens or Corpus Leuteum
Hormones.
 The site of action of progesterone is vaginal epithelium progesterone
receptor.
 Progesterone binds and activates its nuclear receptor, PR, which plays an
important part in the signaling of stimuli that maintain the endometrium
during its preparation for pregnancy.
 Progesterone receptor (PR) is a member of the nuclear/steroid hormone
receptor (SHR) family of ligand-dependent transcription factors that is
expressed primarily in female reproductive tissue as well as the central
nervous system. As a result of its binding its associated steroid hormone,
progesterone, the progesterone receptor (PR) modulates the expression
of genes that regulate the development, differentiation, and
proliferation of target tissues. In humans, PR is found to be highly
expressed in the stromal (connective tissue) cells during the secretory
phase and during pregnancy.
 Progesterone may prevent pregnancy by changing the consistency of
cervical mucus to be unfavorable for sperm penetration, and by
inhibiting follicle-stimulating hormone (FSH), which normally causes
ovulation.
THERAPEUTIC USES
 Treatment of functional uterine bleeding.
 Support pregnancy and fertility.
 Treatment of gynecological problems.
 Menstrual disorders.
 Treatment of habitual and threatened abortion.
BIOSYNTHESIS
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MEDICINAL CHEMISTRY
A = cyclohexanone
B = Cyclohexane
C = Cyclohexane
D = Cyclopentane
 The 4 rings in the structure of progesterone are essential and
unsubstituted, if we replace them or change their position the
therapeutic activity will be terminated.
 The 2 methyl groups present at positions 10 and 13 are essential and
unsubstituted, if we replace them with any other group or change their
position the therapeutic activity will be terminated.
 The acetyl group at position 17 is essential and unsubstituted, if we
replace this with any group or change its position the therapeutic
activity will be terminated.
 The ketonic group at position 3 is essential and unsubstituted, if we
replace this with any group or change its position the therapeutic
activity will be terminated.
ASSAY
 Rapid UV Spectrometry (UV) and Reversed phase high performance
liquid chromatography (HPLC) methods are developed for the
determination of estradiol in preparation.
BRANDS
 Prolutan – Bayer Healthcare
 Progesterone – Geofman Pharmaceuticals
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 Gastron Depot – Global Pharmaceuticals
 Utrogestan – Galaxy Pharma
III. ESTEROGEN
INTRODUCTION
 Estrogen is a female sex hormone which is responsible for the
development maintenance and regulation of the reproductive system
and secondary sex characters in female
 It belongs to the class of estrogens.
 The site of action of estrogen is estrogen receptor (Erα, Erβ, mERs).
 Steroid hormones diffuse through the cell membrane and bind to
specific nuclear receptor. Two estrogen receptor sub types α and β,
mediates the effect of estrogen hormone.
 The transcriptional properties of α and β estrogen receptors are
different. Activated steroid receptor interacts with nuclear chromatin to
initiate RNA synthesis and specific proteins that mediate physiological
function.
THERAPEUTIC USES
 Hormonal contraception
 Hormone Replacement Therapy
 Treat gender dysphoria in transgender women
BIOSYNTHESIS
MEDICINAL CHEMISTRY
A = cyclohexanone
B = Cyclohexane
C = Cyclohexane
D = Cyclopentane
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 The most potent naturally occurring estrogens in humans are 17-β-
estradiol, oestrione and oestriol.
 Each of these molecule is an 18-C steroid containing a phenolic -A ring
(an aromatic ring with hydroxyl group at C-3), and a β-hydroxyl group or
ketone on position 17 of ring -D.
 The phenolic -A ring is the principle structure feature for selective, high
affinity binding to estrogen receptors.
 Most Alkyl substitutions on the phenolic -A ring impair such binding, but
substitution on ring C or D may be tolerated.
 Ethinyl substitution at C-17 position greatly increases oral potency by
inhibiting the first pass hepatic metabolism.
ASSAY
 Rapid UV Spectrometry (UV) and Reversed phase high performance
liquid chromatography (HPLC) methods are developed for the
determination of estradiol in preparation.
BRANDS
 DestroDose – Galaxy Pharma
 Progynon Depot – Bayer Healthcare
 Ovlogyn – Zafa Pharmaceuticals
 Femoston – Abbott Lab
 Globinan – Global Pharma
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IV. ALDOSTERON
INTRODUCTION
 Aldosterone is the main mineralocorticoid steroid hormone produced by
the zona glomerulosa of the adrenal cortex in the adrenal gland.
 It is essential for sodium conservation in the kidney, salivary glands,
sweat glands, and colon.
 Aldosterone plays a central role in the homeostatic regulation of blood
pressure, plasma sodium (Na+), and potassium (K+) levels.
 Binding of aldosterone with the receptors initiates DNA transcription,
initiating transcription of specific proteins resulting an increase in the
number of sodium channels Na+-K+-ATPase molecules.
THERAPEUTIC USES
 Systemic Hypertension
 Hypertensive patients with post MI
 Hypertensive patients with Diabetes Mellitus
 Congestive Heart Failure
BIOSYNTHESIS
MEDICINAL CHEMISTRY
A = cyclohexanone
B = Cyclohexane
C = Cyclohexane
D = Cyclopentane
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GM Hamad
 Steroidal nucleus is essential for steroidal activity.
 Keto group at C-3, carbonyl group at C-20 and double bond between C-4
and 5 is essential for glucocorticoid and mineralocorticoid activity.
 There is α-hydroxyl group is attached at C-17, essential for glucocorticoid
but not for mineralocorticoids. Mineralocorticoid require –OH at C-21.
while glucocorticoids require –OH group at C-11.
BRANDS
 Aldactone– Searle
 Diuton – Medera Pharmaceuticals
V. CORTISOL
INTRODUCTION
 Cortisol is a steroid hormone, in the glucocorticoid class of hormones.
Cortisol is a steroid hormone that regulates a wide range of processes
throughout the body, including metabolism and the immune response.
 It also has a very important role in helping the body respond to stress.
 Cortisol is the major glucocorticoid in humans. It has two primary
actions:
It stimulates gluconeogenesis – the breakdown of protein and fat
to provide metabolites that can be converted to glucose in the
liver
It activates antistress and anti-inflammatory pathways.
THERAPEUTIC USES
 Control blood sugar levels
 Control blood pressure
 Regulate metabolism
 Reduce inflammation
 Assist with memory formulation
BIOSYNTHESIS
71

GM Hamad
MEDICINAL CHEMISTRY
A = cyclohexanone
B = Cyclohexane
C = Cyclohexane
D = Cyclopentane
<
 Naturally occurring glucocorticoids are; cortisone and hydrocortisone.
Synthetics are; prednisolone, methylprednisolone, dexamethasone,
betamethasone etc.
 Conversion of single bond between carbon 1 and 2 to double bond,
increases the anti-inflammatory action and salt & water retention effect
weakens.
 Adding methyl group at C-6 of prednisolone the anti-inflammatory
action enhances and results into methylprednisolone. Thus increased
glucocorticoid activity.
 Adding halogen like F or Cl at C-9 and methyl group at C-16, results in
pronounced anti-inflammatory activity and the salt and water retention
effect also weakens.
 11-beta hydroxyl group is considered to be an important group for
receptor binding. The hydrophilicity and lipophilicity can be changed by
modifications into suitable esters.
BRANDS
 Solu Cortef – Pfizer Laboratories
 Hydrocort – Akhai Pharmaceuticals
 Cortisol – Bio Pharma
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GM Hamad
2. PROTEINOUS HORMONES
INTRODUCTION
 These hormones, like other proteins, are synthesized in cells from amino
acids according to mRNA transcripts.
 Several important peptide hormones are secreted from the pituitary
gland. The anterior pituitary secretes prolactin, adrenocorticotropic
hormone, and growth hormone while posterior pituitary gland secretes
anti-diuretic hormone (vasopressin), and oxytocin.
 Peptide hormones produced by pancreas include glucagon, insulin and
somatostatin, and the gastrointestinal tract are cholecystokinin, gastrin.
CLASSIFICATION OF PROTEINOUS HORMONES
 Classes of proteinous hormones are;
Insulin
Glucagon
Oxytocin
Vasopressin
I. INSULIN
INTRODUCTION
 Insulin is a peptide hormone produced by beta cells of the pancreatic
islets.
MECHANISM OF ACTION
 Insulin regulates both metabolic enzymes and gene expression. It does
not enter cells but initiates a signal that travels from the cell surface
receptor to cytosol and to the nucleus.
 The insulin receptor is a glycoprotein receptor with tyrosine-kinase
activity.
THERAPEUTIC USES
 Type 1 diabetes mellitus
 Post pancreatectomy diabetes
 Gestational diabetes
 Type 2 diabetes mellitus not controlled by diet and exercise
 Failure of oral hypoglycemic agents
CHEMISTRY
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