MODERN DRUG DESIGN

1. By
Naresh .J
Associate Research Analyst –
DDF, Life Sciences India |
Clarivate Analytics

2.  Introduction to Docking(Swayamvaram)
 Abbreviations
 Why We Do Docking
 Molecular Docking in Modern Drug Discovery
 Types of Docking
 Drug design
 Computer-aided drug design (CADD)
1. Structure based drug design (SBDD)
2. Ligand-based drug design (LBDD)
 Drugs design and developement
 Application of Molecular Docking in Modern Drug Discovery
 Conclusion
 References

3.  CADD - Computer Aided Drug Design.
 QSAR - Quantitative Structure Activity Relationship.
 SARs - Structure-Activity Relationships.
 HTS - High Through put Screening.

4.  Docking attempts to find the “best” matching between two molecules.

5.  Drug discovery costs are too high: ~$800 millions, 8~14 years, ~10,000
compounds (DiMasi et al. 2003; Dickson & Gagnon 2004)
 Drugs interact with their receptors in a highly specific and complementary
manner.
 Core of the target-based structure-based drug design (SBDD) for lead
generation and optimization.
Lead is a compound that
– shows biological activity,
– is novel, and
– has the potential of being structurally modified for improved
bioactivity, selectivity.

6. Case Study-
Identification of Inhibitors for Simultaneous Inhibition of AntiCoagulation and
Anti-Infamatory Activities of Snake venom Phospholipase A2. (1994)
169000 compounds
Pharmacophore Based-screening
300 compounds
Molecular docking
32 promising compounds

8.  Drug design, often referred to as rational drug design or simply rational design, is the
inventive process of finding new medications based on the knowledge of a biological target
 Drug discovery cycle highlighting both ligand-based (indirect) and structure-based (direct)
drug design strategies.
HIGH-THROUGHPUT
screening (HTS) is the
process by which large
numbers of compounds
can be tested, in an
automated fashion, for
activity as inhibitors
(antagonists) or activators
(agonists) of a particular
biological target, such as a
cell-surface receptor or a
metabolic enzyme.

9.  The most fundamental goal in drug design is to predict whether a given molecule will
bind to a target and if so how strongly. Molecular mechanics or molecular
dynamics is most often used to estimate the strength of the intermolecular
interaction between the small molecule and its biological target
 Drug design with the help of computers may be used at any of the following stages of
drug discovery:
1. hit identification using virtual screening (structure- or ligand-based design)
2. hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
3. lead optimization of other pharmaceutical properties while maintaining affinity

10.  Virtual screening (VS) is
a computational technique
used in drug discovery to
search libraries of small
molecules in order to identify
those structures which are
most likely to bind to a drug
target, typically a protein
receptor or enzyme.

11. 3D structure of a drug
target interacting with small
molecules is used to guide
drug discovery

12. Ligand-based drug
design
Pharmacophore: A
set of structural
features in a
molecule that is
recognized at a
receptor site and
responsible for that
molecule’s biological
activity Typical
features:
Hydrophobic
Aromatic
H-bond acceptor
H-bond donor
Cationic or anionic
moieties

14.  Determine the lowest free energy structures for the receptor ligand complex.
 Search database and rank hits for lead generation.
 Calculate the differential binding of a ligand to two different macromolecular
receptors.
 Study the geometry of a particular complex.
 Propose modification of a lead molecules to optimize potency or other properties.
 de novo design for lead generation.
 Library design.

15. 1. 1.Molecular docking give the promising contributions to identification and optimization
of ligand in modern drug discovery.
2. 2.The combination of the chemical information of natural products with docking-based
virtual screening will play an important role in drug discovery in the post-genomic era
as more and more new potential targets emerge from the functional genomic studies.
3. 3.Docking-based virtual screening lead to much higher hit rate than traditional
screening methods. (e.g., HTS)

16.  Graham L. Patrick, An Introduction to Medicinal Chemistry 4th edition,
2012 pag. No. 352-356
 Dr. Abdul Wadood , Molecular docking and its application toward modern
drug discovery Dept. of Biochemistry Abdul Wali Khan University.
 Dr. Kumud Sarin, Bioinformatics and its Application in Drug Designing.
 E.M. Krovat, T. Steindl and T. Langer, Recent Advances in Docking and
Scoring,2005 Bentham Science Publishers Ltd.

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