Identification of Gatifloxacin Derivative Asmycobacterium Tuberculosis Dnagyrase Inhibitor Using a Knowledge-Based Computational Molecular Screening Approach

Abstract

Tuberculosis (TB) is a respiratory disease caused by Mycobacterium tuberculosis (MTB) infection. The rapid emergence of MTB strains resistant to numerous antimicrobial drugs is posing a great challenge in controlling the tuberculosis related morbidity or mortality. Therefore, in this study, chemical derivatives of Gatifloxacin (GTF), which could act against the MTB-DNA gyrase enzyme that plays important role in DNA's negative supercoiling during DNA replication, gene expression, and recombination processes, were designed. In this regard, a series of computational molecular screening approaches like sequence extraction and 3D modelling of DNA gyrase and its binding analysis with Gatifloxacin derivatives with molecular dynamics and molecular docking analysis were performed. Findings from molecular docking have concluded GTF-18 (1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl) 1,4-dihydro-3-quinolinyl] carbonyl borodifluoridate) as the best anti-MTB DNA gyrase compound with significant physicochemical properties. This GTF-18 compound demonstrates better affinity towards MTB-DNA gyrase (ΔG is -18.27) compared to parental Gatifloxacin molecule. This study advises future laboratory assays to develop GTF-18 as a novel drug compound for targeting MTB-DNA gyrase.