Inhibitory potential of triazines and hydrazinyl thiazole substituted chromones against the HslVU protease/chaperone complex, a novel drug target.

Abstract

Proteostasis is an important process occurring in all living cells and is highly indispensable for cell survival. The HslVU protease/chaperone complex's critical role in regulating proteostasis to maintain a healthy cellular proteome and its presence in pathogenic microbes made it an important drug target. This study aimed to identify small molecular inhibitors of the HslV protease. Herein, a library of small molecules belonging to the triazine and chromone families has been evaluated for their inhibitory potential against the E. coli HslV protease using both in silico and in vitro techniques. Four compounds, i.e., SHS-II-123a, SHS-II-147a, US-IV-89, and US-IV-92, were identified as potential inhibitors of the HslV protease having IC50 values in the range of 0.1 to 0.32 µM. Additionally, these compounds' drug-likeness and ADMET profiles indicated their compatibility to be considered safer drug candidates. To the best of our knowledge, this is the first report on small molecules having inhibitory effects on the HslVU complex. These identified compounds can be efficiently subjected to further investigations to develop novel and safer antimicrobial agents.