Title: Substrate-product Analogues as Inhibitors of Racemases and Epimerases by Stephen L. Bearne, Dalhousie University, March 21, 2018 at 12:30 pm in Duffy Research Centre, Room 212.

Abstract
Rational approaches for the design of enzyme inhibitors furnish powerful strategies for developing pharmaceutical agents and tools for probing biological mechanisms. I will present a new strategy for the development of gem-disubstituted substrate-product analogues as inhibitors of racemases and epimerases. Some of these enzymes, such as glutamate racemase, serine racemase, and alpha-methylacyl-coenzyme A racemase (AMACR) are targets for the development of therapeutic agents. As one example, I will discuss the development of inhibitors of AMACR, using the Mycobacterium tuberculosis enzyme as a model. The human enzyme is a potential target for the development of therapeutic agents directed against prostate cancer. AMACR binds N,N-dialkylcarbamoyl-CoA substrate-product analogues with affinities that exceed that of the substrate by ~250-fold and that are proportional to the hydrophobicity of the alkyl groups. Overall, the results reveal that gem-disubstituted substrate-product analogues can yield extremely potent inhibitors of an epimerase with a capacious active site.

All are welcome.