Identification of novel inhibitors against Escherichia coli utilizing HisC as a target from histidine biosynthesis pathway

Abstract

Escherichia coli is a gram-negative bacterial pathogen that poses a significant challenge both clinically and epidemiologically. Large numbers of multi-drug resistant E. coli have emerged in the last decade, because of the selection pressure generated by the inadequate use of antibiotics. Although research to combat antibiotic resistance has been going on extensively but still lags in the rate of development of newer antibiotics. Therefore, newer approaches are required to speed up the rate of discovery of antibiotics. Computational methods for screening of inhibitors have made a significant contribution to the discovery of novel antimicrobials. The present study utilized histidinol-phospho aminotransferase (HisC) as a target. HisC is an enzyme that plays a crucial role in the biosynthesis of histidine and its absence in mammals makes it an attractive drug target. A ZINC library of 5000 natural compounds was screened against HisC (PDB ID: 1FG7) using PyRx and the first 500 hits were selected for secondary screening after sorting the result on the basis of binding score. Fifteen compounds passed the secondary filter ADME and out of these five passed toxicity filters; the best among five hits was selected on the basis of its binding score and inhibition constants. Further, molecular dynamics simulations and free binding were computed of selected five compounds and two natural compounds ZINC402598829 and ZINC31157928 complexed with HisC were found as highly stable. Overall, our results indicated that these natural sources could be used as potential HisC inhibitors. Communicated by Ramaswamy H. Sarma