Purine nucleoside phosphorylases as targets for transition-state analog design

Abstract

INTRODUCTION Among the most powerful enzyme-targeted drugs are those that bear a strong resemblance to the transition state of the chemical reaction undergoing catalysis. This chapter illustrates that experimental determination of enzymatic transition-state structure permits chemically stable analogs to be designed. Mimics of these transition states exhibit binding affinities exceeding those of the substrates by factors of greater than 10 6 . To appreciate this approach to drug design, it is necessary to understand the nature of transition-state formation and how it relates to the strong binding interactions between enzymes and transition-state analogs. Enzymatic transition-state formation All chemical reactions proceed through at least one transition state, an unstable structure of maximal energy along the reaction coordinate. Having a lifetime of under 100 fs (10 -13 s), the time required for a single bond vibration, the transition state is the most unstable species along a chemical reaction coordinate. In the absence of a catalyst, the probability of transition-state formation is extremely low. Enzymes achieve great catalytic reaction rates by providing appropriately positioned functional groups within the active site, which interact with and distort the substrate toward the transition state by dynamic motions of the complex. Although the physical means of enzymatic transition-state formation remain the subject of scientific debate, several theories have been proffered. In the early 1940s, Linus Pauling postulated that enzymes bind most optimally not to the normal substrate molecule but rather to the substrate molecule in a strained configuration corresponding to the “activated complex.” He suggested that various attractive forces with the enzyme cause the substrate to adopt the strained configuration, thereby favoring the chemical reaction and accounting for the lowered activation energy of the catalyzed reaction.