Molecular docking, ADME-Tox, DFT and molecular dynamics simulation of butyroyl glucopyranoside derivatives against DNA gyrase inhibitors as antimicrobial agents

Abstract

The emergence of antibiotic resistance highlights the critical need for novel antimicrobial agents. In this study, we investigated the synthesis of methyl α-D-glucopyranoside (1) analogs (2–6) which play vital roles in bacterial replication, in the context of DNA gyrase inhibitors. The unimolar one-step butyroylation of glucopyranoside furnished the 6-O-butyroyl derivative, which was further converted into five newer 6-O-butyroyl-2,3,4-tri-acyl-α-D-glucopyranoside analogs. The newly synthesized chemical structures were determined through physicochemical, elemental, and spectroscopic data. In vitro studies against bacteria and fungi with PASS (activity spectra for substances) prediction showed excellent antimicrobial activity of these glucopyranoside analogs. The cytotoxicity assessment indicated that the compounds exhibited less toxicity. In-depth molecular docking studies were carried out to elucidate the mechanism of action, binding energies, and interaction profiles of the synthesized compounds targeting gyrase. Additionally, a reference molecule, 4-methyl-5-[3-(methylsulfanyl)-1H-pyrazol-5-yl]-2-thiophen-2-yl-1,3-thiazole, was docked into the gyrase receptor to evaluate the inhibitory potential of the synthesized compounds. Moreover, a 100 ns molecular dynamics simulation process was performed to monitor the behavior of the complex structure, and a stable conformation and binding mode were found in the stimulating environment of the compounds. Pharmacokinetic predictions were investigated to evaluate the absorption, distribution, metabolism and toxicity of these compounds, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. In summary, an integrated computational approach combining molecular docking, ADME-Tox assessment, DFT calculations, and molecular dynamics simulations highlights the promise of these derivatives as candidates for the development of new antimicrobial agents targeting DNA gyrase.