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Computer Aided Drug Development Presentation
1. Presented By:
Mr. Rushikesh palkar
First Year M.Pharm
(Dept. of Pharmaceutics)
Sub: COMPUTER AIDED DRUG
DEVELOPMENT
Alard College Of Pharmacy, Pune.
Under the Guidance of:
Dr. Nalanda Borkar
Head of Department
(Dept. of Pharmaceutics)
Alard College Of Pharmacy, Pune.
1
2. Drug Distribution
Drug Excretion
Active Transport
P–gp
BCRP
Nucleoside Transporters
hPEPT1
ASBT
OCT
OATP
BBB–Choline Transporter.
2
3. It is the passage of drug from the circulation to the tissue and
site of its action.
The extent of distribution of drug depends on its lipid
solubility, ionization at physiological pH (dependent on pKa),
extent of binding to plasma and tissue proteins and differences
in regional blood flow, disease like CHF, uremia, cirrhosis.
Movement of drug - until equilibration between unbound drug
in plasma and tissue fluids.
3
4. Definition: Apparent Volume of distribution is defined as
the volume that would accommodate all the drugs in the
body, if the concentration was the same as in plasma.
Expressed as: in Liters
Dose administered IV
V =
Plasma concentration
4
5. Highly lipid soluble drugs – distribute to brain, heart and
kidney etc. immediately followed by muscle and Fats
5
6. Blood brain barrier (BBB): includes the capillary endothelial cells
(which have tight junctions and lack large intracellular pores) and
an investment of glial tissue, over the capillaries. A similar barrier
is loctated in the choroid plexus.
6
7. BBB is lipoidal and limits the entry of non-lipid soluble drugs
(amikacin, gentamicin, neostigmine etc.).
(Only lipid soluble unionized drugs penetrate and have action on
the CNS)
Efflux carriers like P-gp (glycoprotein) present in brain
capillary endothelial cell (also in intestinal mucosal, renal tubular,
hepatic canicular, placental and testicular cells) extrude drugs that
enter brain by other processes. (Inflammation of meanings of
brain increases permeability of BBB)
Dopamine (DA) does not enter brain, but its precursor
levodopa does. This is used latter in parkinsonism.
7
8. Only lipid soluble Drugs can penetrate – limitation of
hydrophillic drugs.
Placental P-gp serves as limiting factor.
But, REMEMBER, its an incomplete barrier – some
influx transporters operate.
Thalidomide.
8
9. Plasma protein binding (PPB): Most drugs possess
physicochemical affinity for plasma proteins. Acidic drugs bind
to plasma albumin and basic drugs to α1-glycoprotein.
Extent of binding depends on the individual compound.
Increasing concentration of drug can progressively saturate the
binding sites.
The clinical significant implications of PPB are:
a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.
b) The PPB fraction is not available for action.
c) There is an equilibration between PPB fraction of drug
and free molecules of drug. 9
10. d) The drugs with high physicochemical affinity for plasma
proteins (e.g. aspirin, sulfonamides, chloramphenicol) can
replace the other drugs(e.g. acenocoumarol, warfarin) or
endogenous compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug long acting,
because bound fraction is not available for metabolism,
unless it is actively excreted by liver or kidney tubules.
f) Generally expressed plasma concentrations of the drug refer
to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g. phenytoin).
10
11. Drugs may also accumulate in specific organs or get bound to
specific tissue constituents, e.g.:
Heart and skeletal muscles – digoxin (to muscle proteins)
Liver – chloroquine, tetracyclines, digoxin
Kidney – digoxin, chloroquine
Thyroid gland – iodine
Brain – chlorpromazine, isoniazid, acetazolamide
Retina – chloroquine (to nucleoproteins)
Iris – ephedrine, atropine (to melanin)
Bones and teeth – tetracyclines, heavy metals
(to mucopolysaccharide of connective tissue)
Adipose tissues – thiopental, ether, minocycline, DDT
11
13. Excretion is a transport procedure which the prototype drug
(or parent drug) or other metabolic products are excreted
Through excretion organ or secretion organ.
Hydrophilic compounds can be easily excreted.
Routes of drug excretion
Kidney
Biliary excretion
Sweat and saliva
Milk
Pulmonary
13
14. Drugs can be excreted in
bile, especially when the are
conjugated with – glucuronic
Acid
• Drug is absorbed glucuronidated or sulfatated in the liver
and secreted through the bile glucuronic acid/sulfate is
cleaved off by bacteria in GI tract drug is reabsorbed (steroid
hormones, rifampicin, amoxycillin, contraceptives)
• Anthraquinone, heavy metals – directly excreted
in colon
14
16. Normal GFR – 120 ml/min].
Glomerular capillaries have pores larger than usual.
The kidney is responsible for excreting of all water soluble
substances.
All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtered.
Glomerular filtration of drugs depends on their plasma protein
binding and renal blood flow - Protein bound drugs are not
filtered !
Renal failure and aged persons. 16
17. Back diffusion of Drugs (99%) – lipid soluble drugs
Depends on pH of urine, ionization etc.
Lipid insoluble ionized drugs excreted as it Is aminoglycoside
(amikacin, gentamicin, tobramycin)
Changes in urinary pH can change the excretion pattern of drugs
Weak bases ionize more and are less reabsorbed in acidic urine.
Weak acids ionized more and are less reabsorbed in alkaline Urine
Utilized clinically in salicylate and barbiturate poisoning – alkanized
urine (Drugs with pKa: 5 – 8)
Acidified urine – atropine and morphine etc. 17
18. Energy dependent active transport – reduces the free
concentration of drugs – further, more drug dissociation from
plasma binding – again more secretion (protein binding is
facilitatory for excretion for some drugs)
OATP – organic acid transport
OCT – organic base transport
P-gp
Bidirectional transport – Blood Vs tubular fluid
Utilized clinically – penicillin Vs probenecid, probenecid
Vs uric acid (salicylate)
• Quinidine decreases renal and biliary clearance of digoxin by
inhibiting efflux carrier P-gp
18
21. Historically ,drug discovery has focused almost exclusively on efficacy and
selectivity against the biological target.
Drug candidates fail at phase II & III clinical trial because of undesirable
drug PK properties including ADME & toxicity.
To reduce the attrition rate at more expensive later stage , in-vitro evaluation
of ADME properties in the early phase of drug discovery has widely adopted.
Many high throughput in-vitro ADMET property screening assay have
developed & applied successfully .
Fueled by ever increasing computational power & significant advance of in
silico modeling algorithms , numerous computational program that aim at
modeling ADMET properties have emerged.
21
22. Transporters should be an integral part of any ADMET modeling program
because of their ubiquitous presence on barrier membranes and the
substantial overlap between their substrates and many drugs.
Unfortunately, because of our limited understanding of transporters, most
prediction programs do not have a mechanism to incorporate the effect of
active transport.
However, interest in these transporters has resulted in a relatively large
amount of in vitro data, which in turn have enabled the generation of
pharmacophore and QSAR models for many of them.
These models have assisted in the understanding of the complex effects of
transporters on drug disposition, including absorption, distribution, and
excretion.
22
23. P-glycoprotein (P-gp) is an ATP-dependent effl ux transporter that
transports anbroad range of substrates out of the cell.
It affects drug disposition by reducing absorption and enhancing
renal and hepatic excretion.
For example, P-gp is known to limit the intestinal absorption of the
anticancer drug paclitaxel and restricts the CNS penetration of human
immunodeficiency virus (HIV) protease inhibitors .
It is also responsible for multidrug resistance in cancer chemotherapy.
Because of its significance in drug disposition and effective cancer
treatment, P-gp attracted numerous efforts and has become the most
extensively studied transporter, with abundant experimental data.
23
24. Ekins and colleagues generated five computational pharmacophore
models to predict the inhibition of P-gp from in vitro data on a diverse set
of inhibitors with several cell systems, including inhibition of digoxin
transport and verapamil binding in Caco-2 cells; vinblastine and calcein
accumulation in P-gpexpressing LLC-PK1 (L-MDR1) cells; and
vinblastine binding in vesicles derived from CEM/VLB100 cells.
By comparing and merging all P-gp pharmacophore models,
common areas of identical chemical features such as hydrophobes,
hydrogen bond acceptors, and ring aromatic features as well as their
geometric arrangement were identified to be the substrate requirements for
P-gp.
Identified transport requirements not only to help screen compounds
with potential effl ux related bioavailability problems, but also to assist
The identification of novel P-gp inhibitors, which when coadministered
with Target drugs would optimize their pharmacokinetic profile by
Increasing bioavailability
24
25. Breast cancer resistance protein (BCRP) is another ATP-dependent effl ux
transporter that confers resistance to a variety of anticancer agents, including
anthracyclines and mitoxantrone
.
In addition to a high level of expression in hematological malignancies and
solid tumors, BCRP is also expressed in intestine, liver, and brain, thus
implicating its intricate role in drug disposition behavior.
Recently, Zhang and colleagues generated a BCRP 3D-QSAR model by
analyzing structure and activity of 25 flavonoid analogs.
The model emphasizes very specific structural feature requirements for
BCRP such as the presence of a 2,3-double bond in ring C and hydroxylation
at position 5. Because the model is only based on a set of closely related
structures instead of a diverse set, it should be applied with caution.
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26. Nucleoside transporters transport both naturally occurring nucleosides and
synthetic nucleoside analogs that are used as anticancer drugs (e.g.,cladribine)
and antiviral drugs (e.g., zalcitabine).
There are different types of nucleoside transporters, including concentrative
nucleoside transporters (CNT1, CNT2, CNT3) and equilibrative nucleoside
transporters (ENT1, ENT2), each having different substrate specificities.
The broad-affinity, low-selective ENTs are ubiquitously located, whereas the
high-affinity, selective CNTs are mainly located in epithelia of intestine,
kidney,liver, and brain [53], indicating their involvement in drug absorption,
distribution, and excretion.
first 3D-QSAR model for nucleoside transporters was generated back in
1990 .
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27. A more comprehensive study generated distinctive models for
CNT1, CNT2, and ENT1 with both pharmacophore and
3DQSAR modeling techniques.
All models show the common features required for nucleoside
transporter mediated transport: two hydrophobic features and one
hydrogen bond acceptor on the pentose ring.
27
28. The human peptide transporter (hPEPT1) is a low-affinity high-capacity
oligopeptide transport system that transports a diverse range of substrates
including β-lactam antibiotics and angiotensin-converting enzyme (ACE)
inhibitors .
It is mainly expressed in intestine and kidney, affecting drug absorption and
excretion. A pharmacophore model based on three highaffinity substrates (Gly-
Sar, bestatin, and enalapril) recognized two hydrophobic features, one
hydrogen bond donor, one hydrogen bond acceptor, and one negative ionizable
feature to be hPEPT1 transport requirements .
The antidiabetic repaglinide and HMG-CoA reductase inhibitor fluvastatin
were suggested by the model and later verified to inhibit hPEPT1 with
Submillimolar potency .
28
29. The human apical sodium-dependent bile acid transporter (ASBT) is a
highefficacy, high-capacity transporter expressed on the apical membrane of
intestinal epithelial cells and cholangiocytes.
It assists absorption of bile acids and their analogs, thus providing an
Additional intestinal target for improving drug absorption.
Baringhaus and colleagues developed a pharmacophore model based on a
training set of 17 chemically diverse inhibitors of ASBT.
The model revealed ASBT transport requirements as one hydrogen bond
donor, one hydrogen bond acceptor, one negative charge, and three
Hydrophobic centers.
29
30. The organic cation transporters (OCTs) facilitate the uptake of many
cationic drugs across different barrier membranes from kidney, liver, and
intestine epithelia.
A broad range of drugs or their metabolites fall into the chemical class of
organic cation (carrying a net positive charge at physiological pH) including
antiarrhythmics, β-adrenoreceptor blocking agents, antihistamines, antiviral
agents, and skeletal muscle-relaxing agents .
Three OCTs have been cloned from different species, OCT1, OCT2, and
OCT3.
A human OCT1 pharmacophore model was developed by analyzing the
extent of inhibition of TEA uptake in HeLa cells of 22 diverse molecules.
The model suggests the transport requirements of human OCT1 as three
hydrophobic features and one positive ionizable feature .
30
31. Organic anion transporting polypeptides (OATPs) influence the plasma
concentration of many drugs by actively transporting them across a diverse
range of tissue membranes such as liver, intestine, lung, and brain .
Because of their broad substrate specificity, OATPs transport not only
Organic anionic drugs, as originally thought, but also organic cationic drugs.
Currently 11 human OATPs have been identified, and the substrate binding
requirements of the best-studied OATP1B1 were successfully modeled with the
metapharmacophore approach recently.
The metapharmacophore model identified three hydrophobic features
flanked by two hydrogen bond acceptor features to be the essential
requirement for OATP1B1 transport.
31
32. The BBB-choline transporter is a native nutrient transporter that transports
choline, a charged cation, across the BBB into the CNS .
Its active transport assists the BBB penetration of cholinelike compounds,
and understanding its structural requirements should afford a more accurate
prediction of BBB permeation.
Even though the BBB- choline transporter has not been cloned, Geldenhuys
And colleagues applied a combination of empirical and theoretical
methodologies to study its binding requirements .
Three hydrophobic interactions and one hydrogen bonding interaction
surrounding the positively charged ammonium moiety were identified to be
important for BBB- choline transporter recognition.
32
33. •Computer application in pharmaceutical research and development, by Sean
Ekins published by john wiley and sons Inc. Assessed Date2021:06(04)
• http://crdd.osdd.net/admet.php Assessed Date2021:06(04)
• https://en.wikipedia.org/wiki/Active_transport Assessed Date2021:06(04)
• https://www.solvobiotech.com/transporters/bcrp Assessed Date2021:06(04)
• https://en.wikipedia.org/wiki/Organic-anion-transporting_polypeptide
Assessed Date2021:06(04)
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