Model Calculations about the Influence of Protic Environments on the Alkylation Step of Epoxide, Aziridine, and Thiirane Based Cysteine Protease Inhibitors

Abstract

Cysteine proteases play pivotal roles in many diseases, making them attractive targets for the development of new drugs. Prominent lead structures for irreversible inhibitors of these enzymes are peptides and peptidomimetics containing the three-membered heterocycles epoxide, aziridine, or thiirane as electrophilic warheads. Until now, no systematic study has been performed to analyze the inherent different inhibition potencies of the three inhibitor types (epoxide, aziridine, thiirane) as well as their different inhibition behavior in dependence of the environment (e.g., pH dependency of inhibition). This is the goal of the present study. By analyzing the computed energy profiles of appropriate model reactions, we investigate to what extent a decreasing pH value changes the mechanisms, the thermodynamics, and kinetics of the irreversible inhibition step. Besides the energies, changes in the geometrical arrangements of the systems are also studied. Additionally, possible influences of entropy effects are estimated and the accuracy of the theoretical approaches is assessed. Our results show that the large enhancement of the inhibition potencies of aziridines at lower pH values results from a strong catalysis even by weak proton donors. For epoxides and thiiranes much lower effects are found.