3. Drug Design SLIDE 3
is the inventive process of finding new
medications based on the knowledge of a
biological target.
It involves the design of molecules that are
complementary in shape and charge to the
biomolecular target with which they interact and
therefore will bind to it.
4. Life Cylce of Drug Design
SLIDE 4
Synthetic or
Natural
Compounds
Preclinical Trails Clinical Trails
1st step 2nd step Drug
3rd step
Traditional Life Cycle
5. Modern Drug Design SLIDE 5
Target
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Target
Verification of
target
Target Selection
Lead
Identificatio
Screen Dnevelopment
High throughput
screening
Secondary assay
Lead
Optimization
Lead explosion
Potency in disease
Pharmacokinetics
Final
1st step 2nd step Drug
3rd step
6. Drug Designing… SLIDE 6
Selected/designed molecule
should be:
Organic small molecule.
Complementary in shape to the
target.
Oppositely charge to the
biomolecular target .
7. Drug Designing… SLIDE 7
This molecule will:
interact with target
bind to the target
activates or inhibits the function
of a biomolecule such as a protein
8. Drug Designing… SLIDE 8
Drug design frequently but not
necessarily relies on computer
modeling techniques.
This type of modeling is sometimes
referred to as computer-aided drug
design.
9. Mechanism based drug
design SLIDE 9
When the disease process is understood
at the molecular level and the target
molecule(s) are defined, drugs can be
designed specifically to interact with
the target molecule in such a way as to
disrupt the disease.
10. Computer-aided drug
design(CADD) SLIDE 10
CADD represents computational
methods and resources that are used to
facilitate the design and discovery of
new therapeutic solutions.
11. Introduction to CADD
SLIDE 11
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.
12. Objective of CADD
SLIDE 12
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)
Integration of testing into design process
Fail drugs fast (remove hopeless ones as early as
possible)
13. Types of drug design
1) Ligand based drug design
SLIDE 13
2)Structure based drug design
14. Ligand-based drug design SLIDE 14
relies on knowledge of other
molecules that bind to the biological
target of interest.
used to derive a pharmacophore
model that defines the minimum
necessary structural characteristics a
molecule must possess in order to
bind to the target.
15. Ligand-based drug design
SLIDE 15
a model of the biological target may be built based on the knowledge of what
binds to it, and this model in turn may be used to design new molecular
entities that interact with the target.
Alternatively, a quantitative structure-activity relationship (QSAR), in which
a correlation between calculated properties of molecules and their
experimentally determined biological activity, may be derived. These QSAR
relationships in turn may be used to predict the activity of new analogs.
16. Structure-based drug design: SLIDE 16
relies on knowledge of the three
dimensional structure of the
biological target obtained through :
1. x-ray crystallography
2. NuclearMagnetic Resonance
(NMR) spectroscopy.
NMR
spectroscopy
X-ray
crystallography
17. Structure-based drug design
SLIDE 17
If an experimental structure of a target is not available,
it may be possible to create a homology model of the
target based on the experimental structure of a related
protein.
Homology modeling, also known as comparative
modeling of protein, refers to constructing an atomic-
resolution model of the "target" and an experimental
three-dimensional structure of a related homologous
protein (the "template").
18. Structure-based drug design
SLIDE 18
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.
various automated computational procedures may be
used to suggest new drug candidates.
19. Methods SLIDE 19
1) Virtual screening:
The first method is identification of new ligands for a given receptor by searching large
databases of 3D structures of small molecules to find those fitting the binding pocket of
the receptor using fast approximate docking programs.
2) de novo design of newligands:
In this method, 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. The key advantage of such a method is that novel structures
can be suggested.
3) optimization of known ligands by evaluating proposed analogs within the binding cavity.
20. Binding site identification
SLIDE 20
It is the first step in structure based design.
relies on identification of concave surfaces
on the protein that can accommodate drug
sized molecules that also possess appropriate
"hot spots" (hydrophobic surfaces, hydrogen
bonding sites, etc.) that drive ligand binding.
21. Docking & Scoring
SLIDE 21
Docking attempts to find the “best”
matching between two molecules
It includes finding the Right Key for
the Lock
To place a ligand (small molecule) into
the binding site of a receptor in the
manners appropriate for optimal
interactions with a receptor.
To evaluate the ligand-receptor
interactions in a way that may
discriminate the experimentally
observed mode from others and
estimate the binding affinity.
22. Components of Docking
SLIDE 22
I- pre- and/or during docking:
Representation of receptor binding site and ligand
II- during docking:
Sampling of configuration space of the ligand-
receptor complex
III- during docking and scoring:
Evaluation of ligand-receptor interactions
23. Advantages of CADD
SLIDE 23
Time
Cost
Accuracy
information about the disease
screening is reduced
Database screening
less manpower is required
24. Success stories of CADD
SLIDE 24
K+ ion channel blocker
structural based discovery
Ca2+ antagonist / T-channel blocker
chemical descriptor based discovery