It's one of the topic of subject Principle Drug Discovery include in M pharm Pharmacology 2nd sem. It include introduction about rational and traditional drug design with types and methods. It'll be beneficial for M pharm Pharmacology students.

1. PRESENTED BY : SAKSHI NALKANDE
M PHARM PHARMACOLOGY( II SEM )
SUB: PRINCIPLE OF DRUG DISCOVERY
Smt. Kishoritai Bhoyar College of Pharmcy
Kamptee, Nagpur.

2.  It is the process in which finding of new
medication based on knowledge of biological
target is done.
 It involve design of small molecular that are
complementary in shape and charge to
biomolecular target.
 The drug is most commonly an organic small
molecule that activate/inhibit the function of
biomolecule such as protein which in turn
result in therapeutic benefit of patient.

3.  Rational drug design can broadly divided into
two categories:
A. Development of molecule with desired
properties for target having known structure and
function.
B. Development of molecule with predefined
properties for target whose structural information
may be or may not be known. The unknown
target identification can be found by global gene
expression data.

4.  Method of rational drug design:
 SAR analysis try to convert structure activity
observation into structure activity relationship.
 We have to aim to identify which molecule
should be synthesize and identify lead
compound for either additional modification or
for pre-clinical studies.
 For Example – Cimetidine
Start with validated biological target and ends
up with drug that optimally interact with target
and triggers the desired biological action.

5.  Problem : Histamine triggers the release of stomach
acid. So want histamine antagonist to prevent stomach
acid = Validated Biological Target.
Step 1 - Chemical modification were made to lead
that is Lead Optimization ( N- guanyl histamine,
Burimamide)
Step 2 – More potent and orally active but thiourea
found to be more toxic in clinical trials
( Metiamide)
Step 3 – Replacement of group lead to an effective
and well tolerated product ( Cimetidine )
Step 4 – Eventully replaced by Zantac with an
improved safety product ( Ranitidine )

6.  Types of Rational Drug Designing Method –
1] Ligand Based Drug Designing
a) QSAR
b) Pharmacohore Perception
2] Structure Based Drug Designing
a) Docking
b) De novo Drug Design

7. 1] Ligand Based Drug Design-
 It relies on the knowledge of other molecules that
bind to the biological target of interest.
 In other words, 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 molecules.
a) In QSAR , biological activity is determied from the
physico-chemical properties of drug. So these QSAR
relationships in turn used in the prediction of
biological activity of new analogues.
Biological Activity= f ( physico-chemical properties)

8. b) Pharmacophore – based Drug Design-
 Examine features of inactive small molecules
(ligands) and the features of active small
molecules (ligands)
 Generate a hypothesis about what chemical
groups on the ligand are necessary for
biological function; what chemical groups
suppress biological function.
 Generate new ligands which have the same
necessary chemical groups in the same 3D
location.

9. 2] Structure Based Drug Design-
 It relies on the knowledge of 3D structure of
the biological target.
 3D structure is obtained by ether X-Ray
crystallography or NMR specctroscopy.
 Using the structure of receptor, candidate
drugs that are predicted to bind with high
affinity and selectivity to the target may be
designed.

10. a) Molecular Docking-
 It is a computational method to predict the
interaction of two molecule generation a binding
model.
 Docking is done between a small molecule and a
macromolecule .
 It is the study of how two or more molecular
structures fit together.
 It is an attempt to find best matching between two
molecules.
 Types of docking- a) Rigid Docking
b) Flexible Docking
c) Manual Docking

11. b) De novo Drug Design-
 It is the process in which 3D structure of
receptor is used to design newer molecules.
 It involves structural determination of the lead
target complexes and lead modifications using
molecular modeling tools.
 Information available about target receptor but
no existing leads that can interact.
 Types of De novo Drug Design-
a) Atom based construction
b) Fragment based construction

12.  It involves the origin of drug discovery that
evolved in natural sources, accidental events.
 It was not target based and not much
systemised.
 Improvement and advancement in
Pharmaceutical science and technology made it
evolutionised to much more systemised
modern DD.

13.  Methods in Traditional Drug Design-
1] Random Screening
2] Trial and Error Method
3] Ethno Pharmacology approach
4] Serendipity Method
5] Classical Pharmacology

14. 1] Random Screening-
 It include random screening of synthetic
compound/natural product by bioassay
procedure.
 It involves two approaches-
a) Screening of selected class of compound like
alkaloid.
b) Screening of randomly selected plants.

15. 2] Trial and Error Method-
It includes berries, roots, leaves and barks that could
be used for medicinal purposes.
For eg- Cinchona barks contain quinine reduced fever
in malaria.
3] Ethno Pharmacology approach-
 It is the study of medicinal plants used in specific
culture groups.
 It involve the observation, description and
experimental investigation of indigenous drugs.

16.  It is based on botany, chemistry, biochemistry,
pharmacology and many other diciplines like
anthropology, archeology and history.
For eg - Andrographis paniculata ( kalmegh )
used for dysentry.
4] Serendipity Method-
Refers to an accidental discovery that is finding
one thing while looking for something else.
For eg – Penicillin by Flaming in 1928 while doing
research on influenza.

17. 5] Classical Pharmacology-
 Also known as function based approach.
 Without prior identification of drug target.
 Anciently drug discovery processes were often
based on measuring a complex response in
vivo such as-
a) Prevention of experimentally induced
seizures.
b) Lowering blood glucose level.
c) Suppression of inflammattory response.
For eg – Discovery of Foxglove in Europe.