Computational studies on the enantioselectivity of α-chymotrypsin towards β-carbomethoxy-γ-lactams

Abstract

In our previous work, racemic β-carbomethoxy-γ-lactams were subjected to enzymatic hydrolysis in the presence of α-chymotrypsin. The hydrolysis of three N-substituted lactams proved to be highly enantioselective, whereas an unsubstituted lactam was recovered in racemic form. Thus, in this paper we applied several molecular modeling protocols to explain the substrate specificity and the enantioselectivity of this enzyme. The adopted procedures involved accurate docking experiments of both enantiomers of each lactam to the protein active site, whose 3-D structure was obtained from X-ray crystallographic data, followed by extensive conformational and energetic analysis of the computer-generated complexes. The results obtained fully account for the experimental evidences on the enantioselective hydrolysis of these interesting, potential drugs by α-chymotrypsin.