Rational design of transition-state analogues as potent enzyme inhibitors with therapeutic applications

Abstract

The structures of the transition states for a variety of enzyme-catalyzed ribosyl group transfer reactions, determined by computational evaluation of multiple tritium and heavy atom kinetic isotope effects on these enzymatic reactions, have been found to show a considerable variation in the extent of bond cleavage at the ribosyl anomeric carbon. The calculated transition-state structures have been used to guide the design of high-affinity transition-state analogue inhibitors for 5′-methylthioadenosine nucleosidases with potential as therapeutic agents. © 2007 American Chemical Society.