Rational drug design is a process that begins with knowledge of a biological target and aims to design small molecules that interact optimally with that target to produce a desired therapeutic effect. It involves analyzing the structures of active molecules and known targets, then designing new molecules that are predicted to specifically fit the target. This may involve modifying existing lead compounds or building new ones de novo. The goal is to develop drugs with greater potency, selectivity and fewer side effects than those found by traditional trial-and-error means. Cimetidine for reducing stomach acid is provided as an example of rational drug design, where it was optimized from an initial histamine analog lead compound.

1. RATIONAL DRUG
DESIGN
Presented by,
J.NARESH.

2. 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
• 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.

3. 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

4. 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-guanyl-
histamine showed some antagonist properties = LEAD compound.

5. Rational Drug Design - Cimetidine
(Tagamet) - continued
a. Chemical modifications were b. More potent and orally active,
made of the lead = LEAD but thiourea found to be toxic in
OPTIMIZATION: 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:

6. 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….

7. 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

8. 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

10. Rational Drug Design - Receptor-based
Drug Design
•Examine the 3D structure of the biological target (usually an X-
ray 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

11. 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 orX-ray crystrollography, is
takenintoaccount as aguide to design anologs.

12. 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.

13. • 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

14. • Antimetabolites : these are the drugs that owing to their
structural resemblance to normal cellular metabolites ,can replace
them in biological process but can not carryout their normal role ,
they are designed by isosteric replacement of certain atoms or
chemical groups of essential metabolites

15. • Antimetabolites:

16. 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.

17. 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.