NOVEL APPROACHES IN

DRUG DESIGN
PRESENTED
BY
Dr. SK. ABDUL RAHAMAN M.Pharm, Ph.D., AIC.

PROFESSOR & HOD

NIRMALA COLLEGE OF PHARMACY

MANGALAGIRI
ANDHRA PRADESH
 INTRODUCTION

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 DRUG DESIGN

• Drug design is the inventive process of finding

new medications based on the knowledge of a
biological target.

• The drug is most commonly an organic small

molecule that activates or inhibits the function
of a biomolecule such as a protein, which in
turn results in a therapeutic benefit to the
patient.
 DRUG DESIGN

• There are two major types of drug design.

1. Ligand-based drug design
2. Structure-based drug design
DRUG DESIGN
 LIGAND BASED DRUG DESIGN

• Ligand-based drug design (or indirect drug design) relies

on knowledge of other molecules that bind to the
biological target of interest.

• Pharmacophore is a group of atoms in the molecule of a

drug responsible for the drug's action.
 LIGAND BASED DRUG DESIGN
• A model of the biological target may be built based on
the knowledge of

• what binds to it ????

• Hydrophobic and hydrophillic groups
• This model in turn may be used to design new
molecular entities that interact with the target.
 LIGAND BASED DRUG DESIGN

• (A) Q SAR
• (B) Analog drug design
• (C) Combinatorial chemistry
• (D) Natural Products as a lead, etc.,
 LIGAND BASED DRUG DESIGN
(A)Q SAR: A quantitative structure-activity relationship (Q SAR),
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.
 electronic, geometric, or steric properties
 LIGAND BASED DRUG DESIGN
(B) Analog drug design:
 Analog design is most fruitful in the study of pharmacologically
active molecules that are structurally specific: their biological
activity depends on the nature and the details of their chemical
structure.
S

N
N Cl

CH3 CH3

CH2CH2CH2 CH2CH2CH2 N
N

CH3 CH3
Imipramine Chlorpromazine

 Hence, a minor modification of the molecule may result in a

profound change in the pharmacological response (increase,
diminish, completely destroy, or alter the nature of the
response).
 LIGAND BASED DRUG DESIGN
 In analog design, molecular modification of the lead compound
can involve one or more of the following strategies:

 Lead compounds are frequently identified as endogenous

participants (hormones, neurotransmitters, second
messengers, or enzyme cofactors) in the body's biochemistry
and physiology.

 A lead may result from routine, random biological screening of

natural products or of synthetic molecules that were created for
purposes other than for use as drugs.
 LIGAND BASED DRUG DESIGN
(i) Bioisosteric replacement
(ii) Design of rigid analogs
(iii) Homologation of alkyl chain(s) or alteration of chain
branching, design of aromatic ring-position isomers,
alteration of ring size, and substitution of an aromatic
ring for a saturated one
(iv) Alteration of stereochemistry, or design of geometric
isomers (or) stereoisomers
(v) Design of fragments of the lead molecule that contain the
pharmacophoric group (bond disconnection)
(vi) Alteration of interatomic distances within the
pharmacophoric group or in other parts of the molecule
 LIGAND BASED DRUG DESIGN
• Bioisosteric replacement strategy has been fruitful in design of
psychoactive agents, by use of the antidepressant
dibenzazepine derivative Imipramine as the lead. The
structural similarity between imipramine and the
phenothiazine antipsychotics [typified by chlorpromazine is
apparent.
S

N
N Cl

CH3 CH3

CH2CH2CH2 CH2CH2CH2 N
N

CH3 CH3
Imipramine Chlorpromazine
 LIGAND BASED DRUG DESIGN

(C) Combinatorial chemistry:

 Combinatorial chemistry comprises chemical
synthetic methods that make possible to prepare large
number (tens to thousands or even millions) of
compounds in a single process.

 These compound libraries can be made as mixtures,

sets of individual compounds or chemical structures
generated in computer.
 LIGAND BASED DRUG DESIGN

The amino acids used in couplings are represented by yellow, blue and
red circles in the figure. Divergent arrows show dividing solid support
resin (green circles) into equal portions, vertical arrows mean coupling
and convergent arrows represent mixing and homogenizing the portions
of the support.
 LIGAND BASED DRUG DESIGN
• Since two decades, so far only one de novo
combinatorial chemistry-synthesized chemical has
been approved for clinical use by FDA (sorafenib, a
multikinase inhibitor indicated for advanced renal
cancer).

• Feher and Schmidt noted that combinatorial

chemistry libraries suffer particularly from the lack of
chirality, as well as structure rigidity, both of which
are widely regarded as drug-like properties.
 LIGAND BASED DRUG DESIGN
(D) Natural Products as a lead:
 A total no. of 520 new pharmaceuticals approved
between 1983 and 1994, among which 39% were
derived from natural products, the proportion of
antibacterials and anticancer agents of which was over
60%.
 Between 1990 and 2000, a total of 41 drugs derived
from natural products were launched on the market by
major pharmaceutical companies including
azithromycin, orlistat, paclitaxel, sirolimus
(rapamycin), Synercid, tacrolimus, and topotecan.
 LIGAND BASED DRUG DESIGN
• During 2001 we have seen the launch of caspofungin
from Merck and galantamine from Johnson &
Johnson, with rosuvastatin, telithromycin,
daptomycin, and ecteinascidin-743 due to follow in
2002.

• The challenge to the medicinal chemist is to exploit

this unique chemical diversity. The following account
illustrates how natural products have been used as
what are called lead compounds, or templates for
the development of important medicines.
 STRUCTURE BASED DRUG DESIGN
 Structure-based drug design (or direct drug design) relies on
knowledge of the three dimensional structure of the biological
target obtained through methods such as x-ray crystallography or
NMR spectroscopy
 Structure based drug design is the one where u design u r
molecules according to the target, here u know the structure of
the receptor i.e target say for example 5HT1A, H1 & H2 and these
target you can download from protien bank and now in docking
softwares like autodock and scigress you can dock your molecules
for best fit on active site and the one which has a good fit gives a
good r2 value.
 STRUCTURE BASED DRUG DESIGN
 The ultimate goal of structure based drug design is a simple
robust process that starts with high resolution crystal structure
of a validated biological macromolecular target and reliably
generates an easily synthesized, high-affinity small molecule
with desirable pharmacological properties.

 High throughput experimental screening methods have become

the workforce for finding hits. A number of rapid structure
based virtual screening methods, called docking can help in
screening large number of molecular libraries for potential hits.
 STRUCTURE BASED DRUG DESIGN
1. Active site identification:
 Active site identification is the first step in this program. It
analyzes the protein to find the binding pocket, derives key
interaction sites within the binding pocket, and then prepares
the necessary data for Ligand fragment link.

 The basic inputs for this step are the 3D structure of the protein
and a pre-docked ligand in PDB format, as well as their atomic
properties.
 STRUCTURE BASED DRUG DESIGN
• Both ligand and protein atoms need to be classified and their
atomic properties should be defined, basically, into four atomic
types:

• (i)Hydrophobic atom: All carbons in hydrocarbon chains (or) in

aromatic groups.
• (ii)H-bond donor: Oxygen and nitrogen atoms bonded to hydrogen
atom(s).
• (iii)H-bond acceptor: Oxygen and SP2 or SP hybridized nitrogen
atoms with lone electron pair(s).
• (iv)Polar atom: Oxygen and nitrogen atoms that are neither H-
bond donor nor H-bond acceptor, sulfur, phosphorus, halogen,
metal, and carbon atoms bonded to hetero-atom(s).
 STRUCTURE BASED DRUG DESIGN
2. Ligand fragment link:
 The term “fragment” is used here to describe the
building blocks used in the construction process. The
rationale of this algorithm lies in the fact that organic
structures can be decomposed into basic chemical
fragments. Although the diversity of organic structures is
infinite, the number of basic fragments is rather limited.
3. Scoring method:
 One early method was developed by Böhm to develop a
general-purposed empirical scoring function in order to
describe the binding energy. The following “Master
Equation” was derived:
 STRUCTURE BASED DRUG DESIGN

Desolvation – enthalpicpenalty for removing the ligand from

solvent
motion – entropic penalty for reducing the degrees of freedom
when a ligand binds to its receptor
configuration – conformational strain energy required to put the
ligand in its "active" conformation
interaction – enthalpic gain for "resolvating" the ligand with its
receptor
STRUCTURE BASED DRUG DESIGN
 DEFINING THE BINDING POCKET

Interaction site:
Coat one region of the protein with polar and steric probes
Define positions for:
H-donor
H-acceptor
Lipophilic-aliphatic
Lipophilic-aromatic
STRUCTURE BASED DRUG DESIGN
 STRUCTURE BASED DRUG DESIGN
(A)Computer Aided Drug Design
(B) Rational Drug Design
(A) Computerised Drug Design:
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: optimization of other pharmaceutical
properties while maintaining affinity
 STRUCTURE BASED DRUG DESIGN
(B) Rational Drug Design:
 A drug target is a key molecule involved in a particular metabolic
or signaling pathway that is specific to a disease condition or
pathology or to the infectivity or survival of a microbial
pathogen.

 The first unequivocal example of the application of structure-

based drug design leading to an approved drug is the carbonic
anhydrase inhibitor dorzolamide, which was approved in 1995.

 Another important case study in rational drug design is imatinib,

a tyrosine kinase inhibitor.
 STRUCTURE BASED DRUG DESIGN
 Cimetidine, the prototypical H2-receptor antagonist from
which the later members of the class were developed
 Selective COX-2 inhibitor NSAID’s,
 Dorzolamide, a carbonic anhydrase inhibitor used to treat
glaucoma,
 Enfuvirtide, a peptide HIV entry inhibitor
 Nonbenzodiazepines like zolpidem and zopiclone,
Probenecid, SSRIs (selective serotonin reuptake inhibitors)
 Zanamivir, an antiviral drug,
 Isentress, HIV Integrase inhibitor, etc.,
 CHOLECYSTOKININ ANTAGONIST
 A Cholecystokinin antagonist is a specific type of receptor
antagonist which blocks the receptor sites for the peptide
hormone Cholecystokinin (CCK).
 There are two subtypes of this receptor known at present,
defined as CCKA and CCKB (also called CCK-1 and CCK-2).

 CCKA is mainly expressed in the small intestine, and is involved

in the regulation of enzyme secretion by the pancreas, secretion
of gastric acid in the stomach, intestinal motility and signalling
of satiety (fullness).
 CHOLECYSTOKININ ANTAGONIST

 CCKB is expressed mainly in the central nervous

system, and has functions relating to anxiety and the
perception of pain. Antagonists for the CCK receptors
can thus have multiple functions in both the gut and
brain.

 CCK is actually a family of hormones identified by

number of amino acids, e.g., CCK58, CCK33, and
CCK8. CCK58 assumes a helix-turn-helix
configuration.
 CHOLECYSTOKININ ANTAGONIST
 Selective CCKA antagonists such as lorglumide and
devazepide have been developed both for their anti-
ulcer effects and as potential drugs to limit the
development of gastrointestinal cancers such as
colon cancer.
 CCK antagonist is the non-selective antagonist
proglumide, which blocks both CCKA and CCKB, and
was originally developed for the treatment of
stomach ulcers. This action derived from its blockade
of CCKA in the gut and consequent reduction in
secretion of gastric acid
 CHOLECYSTOKININ ANTAGONIST

lorglumide proglumide

sodium;4-[(3,4-dichlorobenzoyl)amino]- (4-Benzamido-N,N-dipropylglutaramic acid

5-(dipentylamino)-5-oxopentanoate
 CONCLUSION
 Even though new high-throughput technologies have been
developed generating large amounts of genomic data, drug design
has not followed the same development and it is still complicated
and expensive to develop new single-target drugs.
 In contrast, new findings suggest that multi-target drugs not only
maximize the number of possible points of action but also
introduce novel network disruption and systems-oriented
strategies.
 Therefore, multi-target drug design combined with a network-
dependent approach create a promising concept to combat
diseases based on multi-genetic disorders such as cancer, and
diseases that involve a variety of cell types such as
immunoinflamatory disorders and diabetes.
THANK U