Modeling of the Reaction Mechanism of the Decomposition of a New Class of Mechanism­-Based Protease Inhibitors

Abstract

Abstract: Investigating the hydrolytic stability of mechanism-based inhibitors such as peptidyl 0-acyl hydroxamates we found that peptidyl hydroxamates with proline in P1-position are up to 3 orders of magnitude more stable than those with other residues in this position. Semiempirical AMI calculations have been carried out for the comparison of proline and glycine containing hydroxamates and on their corresponding anions. The theoretical calculations indicate an interaction between the N-terminal amide hydrogen with the negatively charged carboxamide function of the glycine anions. Such an arrangement is not possible in the case of the proline analogues. Based on these results an explanation of the remarkable difference of the rate constants due to different decomposition mechanisms of the 0-benzoyl-N-acetyl aminoacyl hydroxamates can be given.