3. 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
3
4. 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.
4
5. › 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).
5
6. 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.
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7. › 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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8. 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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9. 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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10. 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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11. 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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12. 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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14. Rational Drug Design;
Example - Cimetadine (Tagamet)
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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.
15. Rational Drug Design – Cimetidine (Tagamet) - continued
15
a. Chemical modifications
were made of the lead =
LEAD OPTIMIZATION:
b. More potent and orally
active, but thiourea found to
be toxic in clinical trials
c. Replacement of the group led to
an effective and well-tolerated
product:
d. Eventually replaced by Zantac
with an improved safety profile
16. Rational Drug Design -
16
Begins with the design of compounds that conform to
specific requirements. The molecules are synthesized, tested.
Then the molecule is redesigned, synthesized, tested….
17. 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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18. 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)
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Advantage:
Don’t need to
know the
biological target
structure
20. •Examine the 3D structure of
the biological target (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.
Advantage: Visualization allows direct
design of molecules
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21. 21
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.
22. 22
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.
23. 23
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
24. 24
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.
25. 25
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.
