Computer-Aided Drug Design

1. Advances In Silico Approaches on Data Analysis,
Disease Diagnostics and Dark Proteome.
PRESENT BY- FAIZAN AHMED HILAL

2. What are Drugs
• A drug is any substance (with the exception of
food and water) which, when taken into the
body, alters the body’s function either
physically and/or psychologically.

3. Sources of Drugs
• Nature as source of drugs
Nature is one of the most powerful and primitive source of drug which
includes plants, animals, Minerals, and microbial sources. The drugs
derived from nature are called Natural products.
 Plant source
In ancient times, the vast majority of traditionally used crude drugs in
Western medicine were plant-derived extracts. This has resulted in a pool
of information about the potential of plant species as an important source
for drug discovery.

4. • Animal source
Animals are also the important sources of drugs. For example,
Pancreas is a source of Insulin which is used in treatment of
Diabetes. More examples are- Sheep thyroid is a source of
thyroxin, used in hypertension and other thyroid disorders
• Mineral source
Some examples of mineral sources are- Fluorine which has
antiseptic properties, Iron used in iron deficiency anemia,
Iodine as antiseptics, Gold salts in rheumatoid arthritis etc..

5. • Microbial source
Microbes are the main source of antimicrobial drugs. For example,
Actinobacteria gives Streptomycin which has been a source of antibiotics
since long back. The other classical example of an antibiotic discovered as
a defense mechanism is Penicillium notatum, a fungus which produces
Penicillin
 Combinatorial chemistry
Combinatorial chemistry is other key source of medicinal chemistry
enabling the efficient generation of huge libraries for the need of high-
throughput screening. After two decades of combinatorial chemistry it has
been observed that despite the enormous efficiency of chemical
compounds, no remarkable increase in lead or drug candidates have been
reached. The natural products still play a major role as starting material for
drug discovery

6. Drug discovery
• Drug discovery is the process through which potential new
medicines are identified. It involves a wide range of scientific
disciplines, including biology, chemistry and pharmacology

7. Computer Aided Drug Design
• Use of computational approaches to discover, develop, and
analyze drugs and similar biologically active molecules.

8. Introduction to CADD
• Drug design with the help of computers may be used
at any of the following stages of drug discovery
• Hit identification using virtual screening(structure- or
ligand based design)
• Hit to lead optimization of affinity and
selectivity(structure-based design, QSAR, etc)
• Lead Optimization: optimization of other
pharmaceutical properties while maintaining affinity.

9. Aim of CADD
• To change from:
• Random Screening against disease assays
• Natural products, synthetic chemicals
To
 Rational drug design and testing
 Speed-up screening process
 Efficient screening(focused, target directed)
 De novo design(target directed)
 Fails drugs fast (remove hopeless ones as early as possible)

10. Drug Designing Approaches
1. Ligand Based Approach
2. Target Based Approaches
3. De novo Approaches
4. Structure Based Drug Design

11. Ligand Based Approach
 These are used when the receptor is not known
 Ligand Based approaches try to identify
characteristics common to known ligands to use
in screening for new or improved drugs
 If a set of active ligands molecules is known for
the macromolecular target, but little or no
structural information exists for the target , ligand
based computational method can be employed

12. There are Two methods to do this
• Quantiative structure activity relationship(QSAR)
• Pharmacophore Method
Is the Specific 3-d arrangement of functional groups within a molecular
framework that are specifically binds to a macromolecule or an enzyme
active site.
Identifiaction of pharmacophore is an important step in the interaction
between a receptor and a ligand

13. Target Based Approaches
• Target Based drug design methods based on the
structure of the biological target either bound or
unbound to an inhibitor or substrate
• Target based design methods are also known as
structure based or Rational design methods
• Docking involves scanning a database of known
molecules for those likely to bind well to the receptor

14.  Docking is used to generate possible binding
geometries and can evaluate using scoring
function.
 The Method may also involve some
refinement of the intially generated
conformations before or after scanning

15. De novo Approaches
• De novo design is the approach to build a
customized ligands for a given receptor
• This approach involves the ligand optimization
• Ligand Optimization can be done by analyzing
protein active site properties that could be
probable area of contact by the ligand

16. • The Analyzed active site properties are
described to negative image of protein such as
hydrogen bond, hydrogen bond acceptor and
hydrophobic contact region.

17. Structure based drug design
• Structure-based drug design(also known as
rational drug design) is a techniques that
accelerates the drug discovery process
• It has been estimated that sbdd can reduce
the cost from target indentification to
investigational new drug filling by 50 %
• The technique requires high resolution 3-d
structure of the inhibitor bound to the target
obtained using x-ray crystallography.

18. • once the structure is obtained, the interactions
between the inhibitor and the active site of the
target are analyzed. Improved inhibitors result
from the analysis, resulting in a shortening of the
lead optimization process
• Rational drug design is a method for developing
new pharmaceuticals that typically involves the
elucidation of fundamental physiological
mechanisms.

19. Steps in drug designing
1. Target Identification
2. Target validaiton
3. Lead Identification
4. Lead Optimization
5. Docking
6. Analysis

20. Drug Discovery: a process by which a drug candidate is identified and
partially validated for the treatment of specific disease.
• Mechanism of action
• Target Identification/Validation
• Lead identification/optimisation
• ADME propertied
• PK/PD
• Toxicity

21. Drug discovery process does not include:
• Preclinical studies,
• Clinical trials
• Regulatory approval,
• Sales and marketing.
• These are all called drug development process