Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin L.

ABSTRACT: Cathepsin L (CatL) is a lysosomal cysteine protease whose activity has been related to several human pathologies. However, although preclinical trials using CatL inhibitors were promising, clinical trials have been unsuccessful up to now. We are presenting a study of two designed dipeptidyl keto Michael acceptor potential inhibitors of CatL with either a keto vinyl ester or a keto vinyl sulfone (KVS) warhead. The compounds were synthesized and experimentally assayed in vitro, and their inhibition molecular mechanism was explored based on molecular dynamics simulations at the density functional theory/molecular mechanics level. The results confirm that both compounds inhibit CatL in the nanomolar range and show a time-dependent inhibition. Interestingly, despite both presenting almos

SUBMITTER: Fernandez-de-la-Pradilla A 

PROVIDER: S-EPMC10594577 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature