Identification of novel DNA gyrase B inhibitors in Mycobacterium species using integrated computational approaches

Drug-resistant Mycobacterium tuberculosis remains a major global health challenge, particularly due to the emergence of multidrug-resistant and extensively drug-resistant strains. DNA gyrase, specifically the ATPase domain of GyrB, represents a promising target for the development of novel anti-tubercular agents.

A comprehensive computational workflow was employed, including pharmacophore-based virtual screening of approximately 1,000,000 compounds from the PubChem, ZINC, ChEMBL, and MolPort databases. Hits were filtered using Lipinski's rule of five, structural diversity analysis, molecular docking, ADMET and toxicity assessment, molecular dynamics simulations, and density functional theory analyses.

Approximately 30,000 preliminary hits were obtained, which were reduced to 21 candidate molecules and subsequently to 10 unique compounds. Molecular docking identified two lead compounds, D (PubChem ID: 166484985) and I (PubChem ID: 166484904), with strong binding affinity toward the GyrB ATPase domain. ADMET and toxicity analyses indicated favorable drug-likeness and safety profiles. Molecular dynamics simulations and density functional theory studies further confirmed stable protein-ligand interactions and significant electronic reactivity.

Compounds D and I demonstrated promising ATP-competitive inhibition of the GyrB ATPase domain and exhibited distinct species-specific interaction profiles. These findings support their potential as novel anti-tubercular lead scaffolds for further experimental validation and therapeutic development.