Computational approach towards the design of novel inhibitor against universal stress protein A to combat multidrug resistant uropathogenic Escherichia coli

Uropathogenic Escherichia coli is one of the primary causative agent of urinary tract infections (UTIs), poses a threat to public health globally. Antibiotics are the only options for the treatment however emergence of multidrug resistance (MDR) necessitates search for alternative therapeutics. Administration of antibiotics generated oxidative stress in this MDR pathogen and enhanced the expression of Universal stress proteinA (UspA) that helped to overcome the stress and assisted in cell survival. The aim of the study was to design drug candidates against UspA by in silico approach. Three-dimensional structure of UspA protein, was homology modelled and screened against a library of 100,00 0 molecules shortlisted based on Lipinski's rule and optimum molecular weight selection for good inhibitors from 7.4 million drug like molecules of ZINC database to discover most potent UspA inhibitors. Three potent virtual hits were identified based on their different cut-offvalues as binding energy, hydrogen bonding, and ADMET properties. The stability of the protein-ligand complex was investigated using MD simulation study across 100 ns time scale. The results indicated that amongst the three potent molecules ZINC00 0104153710 was found to be the best fit lead molecule which has showed a high affinity for the catalytic region of UspA, and formed strong hydrophobic and polar interactions with the amino acid side chains involved in the binding site. From this study it is concluded that ZINC00 0104153710 molecule may act as a reliable inhibitor of UspA and may be used to develop a drug against the MDR uropathogenic E.coli. (C) 2021 Elsevier B.V. All rights reserved.