RATIONAL DRUG DESIGN

Presented by,

J.NARESH.

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.

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

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.

Rational Drug Design - Cimetidine (Tagamet) - continued

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:

a. Chemical modifications were made of the lead = LEAD OPTIMIZATION:

d. Eventually replaced by Zantac with an improved safety profile

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….

3)Computer –assisted drug design(CADD)

4) Molecular graphics

5)Pattern recognition

6)Receptor -fit

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)

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

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

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.

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.

• 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

• 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

• Antimetabolites:

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.

References: Andrejus Korolkovas ESSENTIALS OF MEDICINAL CHEMISTRY, 2ND EDFriary, 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.