Prof. Babu Tekwani, University of Mississippi

Chiral Switches for New Drug Discovery: Optimization of Pharmacologic & Safety Profiles

Biochemistry Division Seminar Series

The effect of isomerism on biological activity and toxicity of drugs is well documented. Enantioselectivity is an important feature of the living world. Chiral centers are common in biomolecules, which are made up of units that have the same sense of chirality. Essential physiological processes are homochiral. They typically show 100% stereoselectivity and involve only one of the possible enantiomers. When exogenous compounds including therapeutics are introduced into the body, biological targets show a high degree of chiral discrimination. Effects of different enantiomers are often markedly different. Differential interaction of enantiomers with chiral targets, such as receptors, enzymes, transporters and other biomolecules and enantioselective ADME-PK/PD profiles form the molecular basis for this enantioselectivity. De novo development of a drug in enantiomerically pure form, and “switch” from an existing racemic drug to one of its isomers are now common approaches in drug development. FDA recommends evaluation of both enantiomers as well as racemic mixtures of a chiral drug before its introduction into the clinic. From any perspective – regulatory, scientific, and humanitarian – use of a chiral drug in racemic form is not acceptable. In several cases, chiral switches have allowed remarkable improvements in therapeutic profile of current drugs. The chiral switches are also being exploited to allow line of extension of blockbuster drugs. While we can empirically determine which enantiomer has a better safety to efficacy profile, it is important to understand the molecular bases of these advantages, and to rationally apply them to optimize pharmacologic & safety profiles of drugs.

For more information contact Prof. Adegboyega Oyelere (404-894-4047).