RATIONAL

DRUG DESIGN
DRUG DISCOVERY AND
DEVELOPMENT

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 Rational Drug design
 Rational drug design is also sometimes referred as
Drug design or Rational design. It is a process in
which finding of new medication based on
knowledge of biological target is done. It involves
design of small molecules that are complementary
in shape and charge to bimolecular target.
 The drug is most commonly an organic small
molecule that activates or inhibits the function of a
bio molecule such as a protein, which in turn
results in a therapeutic benefit to the patient

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 In contrast to traditional methods
of drug discovery, which rely on
trial-and-error testing of chemical
substances on cultured cells or
animals, and matching the
apparent effects to treatments,
rational drug design begins with a
hypothesis that modulation of a
specific biological target may
have therapeutic value.
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› Drug design frequently but not necessarily relies
on computer modeling techniques.
› This type of modeling is often referred to as
computer aided drug design.
› Finally, drug design that relies on the knowledge of
the three-dimensional structure of the bio
molecular target is known as structure-based drug
design.
› The phrase “drug design” is to some extent a
misnomer.
› A more accurate term is ligand design (i.e., design
of a small molecule that will bind tightly to its
target).
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BACKGROUND
› Biomolecular target (proteins or nucleic
acids) is a key molecule involved in a
particular metabolic or signaling pathway
that is leading to a specific disease
condition or pathology or to the
infectivity or survival of a microbial
pathogen.
› In Some cases, small molecules will be
designed to inhibit the target function in
the specific pathway (diseased state).
› Small molecules (inhibitors or
modulators) will be designed that are
complementary to the active
site/allosteric site of target. 6
› In some other cases, small
molecules will be designed or
developed to enhance the normal
pathway by promoting specific
biomolecular molecules in the
normal pathways that may have
been affected in the diseased
state.

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 Drug Design
Two ways:
1. Development of ligands with desired
properties for targets having known structure
and functions.
2. Development of ligands with predefined
properties for targets whose structural
information may be or may not be known.
This, unknown target information can be found
global gene expression data.

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 First Generation Rational
Approach in Drug Design
› In 1970s the medicinal chemists considered
molecules as topological entities in 2
dimension (2D) with associated chemical
properties.
› QSAR concept became quite popular. It was
implemented in computers and constituted
first generation rational approach to drug
design

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 2nd Generation Rational
Approach in Drug Design
› The acceptance by medicinal chemists of
molecular modeling was favored by the fact
that the QSAR was now supplemented by 3D
visualization.
› The “lock and key” complementarily is actually
supported by 3D model. Computer aided
molecular design (CAMD) is expected to
contribute to intelligent lead .

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 Evolutionary Drug
Designing
› Ancient times: Natural products with biological
activities used as drugs.
› Chemical Era: Synthetic organic compounds
› Rationalizing design process: SAR &
Computational Chemistry based Drugs
› Biochemical era: To elucidate biochemical
pathways and macromolecular structures as
target as well as drug.

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 Method of Rational drug
design
› SAR analysis try to convert structure- activity
observations into structure-activity
relationships. We have to aim at maximizing
the knowledge that can be extracted from the
raw data in molecular terms, exploit this
knowledge to identify which molecule should
be synthesized ant identify lead compounds
for either additional modification or further
pre-clinical studies

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INITIAL KNOWLEDG OPTIMIZ CLINICAL
SAR
LEAD E ED LEAD DEVELOPME
NT

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Rational Drug Design;
Example - Cimetadine
(Tagamet)
Starts with a validated biological target and ends up
with a drug that optimally interacts with the target and
triggers the desired biological action.
Problem: histamine triggers release of stomach acid.
Want a histamine antagonist to prevent stomach acid
release by histamine = VALIDATED BIOLOGICAL
TARGET.

Histamine analogs were synthesized with

systematically varied structures (chemical
modification), and SCREENED. N-guanylhistamine
showed some antagonist properties = LEAD
compound. 14
 Rational Drug Design – Cimetidine (Tagamet) -
continued
a. Chemical modifications b. More potent and orally
were made of the lead = active, but thiourea found to
LEAD OPTIMIZATION: be toxic in clinical trials

c. Replacement of the group led to d. Eventually replaced by Zantac

an effective and well-tolerated with an improved safety profile
product:

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 Rational Drug Design -
Begins with the design of compounds that conform to
specific requirements. The molecules are synthesized, tested.
Then the molecule is redesigned, synthesized, tested….

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Types of Rational Drug Designing
Methods:
1. 3D structure of biological target (receptor-
based drug design)
2. Structure(s) of known active small molecules
(pharmacophore-based drug design)
3)Computer –assisted drug design(CADD)
4) Molecular graphics
5)Pattern recognition
6)Receptor -fit

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Rational Drug Design -
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 locations. (“Mimic” the active groups)

Advantage:
Don’t need to
know the
biological target
structure

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•Examine the 3D structure Advantage: Visualization allows
of the biological target direct design of molecules
(usually an Xray structure;
hopefully one where the
target is complexed with a
small molecule ligand; if
no data is available, look
for homologous protein
structures/sequences.)
•Look for specific chemical
groups that could be part
of an attractive interaction
between the target protein
and the drug..
Design a drug candidate
that will have multiple
sites of complementary
interactions with the
biological target.
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3)Computer-assisted drug design:
This is concerned primarily with physicochemical parameters
involved in drug activity, quantitative structure –activity
relationship (QSAR) and quantam chemistry models ,to determine
the most promising substance of a series.

4)Molecular graphics:
It also called molecular modeling and conformational analysis. In
which the conformation or molecular shape of drug, sometimes
determined by computer or X-ray crystrollography, is taken into
account as aguide to design anologs.

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5) Pattern recognition: this method is used to save time and
money in selecting the best option for the synthesis of potential
desired drugs.

6) Receptor-fit: this is also called pharmacological receptor

characterization , in which several modern techniques are used ,
including NMR spectroscopy, to ascertain how drug-receptor
interaction may take place and based on this information , design
a drug that may be considered as a template of receptor.

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Examples of the drug that are synthesized by using
rational drug design method.
• Antidotes: to neutralize the effect of toxic warfare agent Lewisite
,dimercaprol, called British anti-Lewisite (BAL) was prepared on
assumption, which proved to be correct

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Enzyme Inhibitors: in this approach it is imperative to know
the various steps involved and to try to inhibit preferentially the rate
limiting step , enzyme inhibitors introduced by this means ,
especially through isosteric replacement in the molecules of enzyme.
Eg: Allopurinol . An inhibitor of xanthene oxidase enzyme and
prevent the synthesis of the uric acid, used in treatment of gout.

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References:
Andrejus Korolkovas ESSENTIALS OF MEDICINAL CHEMISTRY, 2ND ED
Friary, R. Jobs in the Drug Industry A Career Guide for Chemists; Academic Press: San
Diego, CA, 2000.
Thomas, G. Medicinal Chemistry An Introduction; John Wiley & Sons: New York, NY,
2000.
Williams, D. A.; Lemke, T.L. Foye's Principles of Medicinal Chemistry; Lippincott
Williams & Wilkins: Baltimore, MD, 2002.

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