Virtual High-Throughput Screening of Malaysian Phytochemicals Targeting DNA Gyrase B in Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) remains a significant global health concern, particularly as the prevalence of multi-drug resistant strains increases. An established target for innovative anti-TB therapies is the enzyme DNA Gyrase B (GyrB), essential for bacterial DNA replication. This research, Malaysian phytochemicals sourced from the NADI database were examined as potential GyrB inhibitors. Molecular docking studies were conducted to identify ligands that exhibit strong binding affinity to the ATP-binding pocket of GyrB. The protein-ligand interactions were analyzed using LigPlot+, revealed the formation of critical hydrogen bonds and hydrophobic contacts. Notable phytochemicals such as MSC1992 (binding energy of –9.7 kcal/mol), MSC2085 (–9.2 kcal/mol), and MSC2259 (–9.2 kcal/mol) demonstrated significant binding energies. The interaction analysis confirmed stable interactions at the active site, specifically with hydrogen bonds to residues Glu56 and Asp79, alongside hydrophobic interactions with Ile84 and Val99. Further assessments through ADMET profiling indicated that MSC1992, MSC2085, and MSC2657 fulfilled the criteria set by Lipinski's rules, all exhibited molecular weights under 500 Da, LogP values ranging from 2.0 to 2.4, and favorable hydrogen bond donor and acceptor ratios. Additionally, these ligands displayed low predicted toxicity levels and minimal CYP450 inhibition, suggesting potential for oral taken. The combination of docking studies, interaction mapping, and comprehensive ADMET profiling presents Malaysian phytochemicals as promising scaffolds for the inhibition of GyrB. This approach underscores the significance of biodiversity in drug discovery and positions the research as a compelling candidate for further exploration in medical biotechnology, potentially leading to molecular dynamics simulations and experimental validations in the future.