Determining the 3-substituted Coumarins inhibitory potential against the HslV protease of E. coli.

OBJECTIVE: The growing bacterial resistance towards classical antibiotics demands the development of novel approaches for the effective treatment of potentially fatal bacterial infections in humans. Proteostasis is crucial for the survival of every living cell, as several important physiological functions depend on well-regulated proteostasis. Within bacteria, the regulation of proteostasis relies on AAA+ (Adenosine 5'-triphosphatases associated with diverse cellular activities), ATPases, such as the HslVU complex (heat shock locus gene products U and V), along with other proteases. The HslVU protease/chaperon complex is thought to be the progenitor of the eukaryotic proteasome that regulates proteostasis mostly in prokaryotes. This study aimed to determine the inhibitory potential of 3-substituted coumarin derivatives against Escherichia coli heat shock locus V (HslV) protease. MATERIALS AND METHODS: In this study, twenty-three derivatives of 3-substituted coumarin were assessed for their inhibitory potential against E. coli HslV protease using both in-vitro and in-silico techniques. RESULTS: Among all the tested compounds, US-I-64, US-I-66, US-I-67, and US-I-68 displayed notable inhibitory potential against the HslV protease, showing IC50 (half maximal inhibitory concentration) values ranging from 0.2 to 0.73 µM. Additionally, the inhibitory potential of these compounds against the eukaryotic proteasome was also evaluated using a separate in-silico study. It was found that these compounds did not bind with the proteasomal active site, suggesting no apparent side effects of these lead molecules. CONCLUSIONS: These identified HslV protease inhibitors can be used for the development of novel and safer anti-bacterial drugs.

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

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

Correction to: European Review for Medical and Pharmacological Sciences 2022; 26 (22): 8567-8575. DOI: 10.26355/eurrev_202211_30392-PMID: 36459037-published online on November 30, 2022. After publication, the authors applied some corrections to the text: - Dr. U. Salar's affiliation has been corrected as follows: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan. - The values in the row "Binding energy with HsIV (Kcal/mol)" Table I have been corrected as follows: from -8.4 into -9.0; from -8.6 into -9.2; from -8.0 into -8.5 from -8.3 into -8.7. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/30392.