L-Captopril and its derivatives as potential inhibitors of microbial enzyme DapE: A combined approach of drug repurposing and similarity screening

The perils of antimicrobial drug resistance can be overcome by finding novel antibiotic targets and corresponding small molecule inhibitors. Microbial enzyme DapE is a promising antibiotic target due to its importance to the bacterial survival. The potency of L-Captopril, a well known angiotensin-converting enzyme inhibitor, as an inhibitor of DapE enzyme has been evaluated by analyzing its binding modes and binding affinity towards DapE enzyme. L-Captopril is found to bind the metal centers of DapE enzyme either via its thiolate group or through its carboxylate group. While the latter binding mode is found to be thermodynamically favorable, the former binding mode, also seen in the crystal structure, is kinetically favored. To optimize the binding affinity of the inhibitor towards DapE enzyme, a series of LCaptopril-based inhibitors have been modelled by changing the side groups of L-Captopril. The introduction of a bipolar functional group at the C4 position of the pyrrolidine ring of L-Captopril and the substitution of the thiol group with a carboxylate group, have been shown to provide excellent enzyme affinity that supersedes the binding affinity of DapE enzyme towards its natural substrate, thus making this molecule a potential inhibitor with great promise. (C) 2018 Elsevier Inc. All rights reserved.