Unlocking potent inhibitors for <i>Mycobacterium tuberculosis</i> NaMN adenylyltransferase: a multi-database exploration through integrated structure and ligand-based pharmacophore modelling, dynamics and energetic analysis

Ability of mycobacteria to develop resistance against new antibiotics is demanding novel screening methodologies beyond conventional methods for new anti-tubercular drugs. Enzymes of NAD biogenesis in mycobacteria present a viable therapeutic target for both latent and active tuberculosis. It has recently been demonstrated that NaMN adenylyltransferase is an essential enzyme for mycobacterial survival. We present here the pharmacophore-based virtual screening strategies to find potential inhibitors against the NaMN adenylyltransferase. Pharmacophores were designed using benzimidazolium derivatives which occupy a unique site inducing the formation of dimer of dimers of NaMN adenylyltransferase and blocking its activity. Several such compounds exhibited high affinity binding to the NaMN adenylyltransferase structure, distinguishing them as high-scoring inhibitors. Further, molecular dynamics simulations along with MM-PBSA calculations were performed to evaluate them. Notably, ZINC34698873 from ligand-based pharmacophore modelling and CCG30319 from structure-based pharmacophore modelling both showed substantial binding and inhibitory effects against this enzyme. Simulation results indicate that these possible inhibitors were able to effectively adopt and form stable complexes within the binding pocket. Furthermore, the assertion that these molecules create strong contacts with dimer interface region residues were further supported by the low binding energy obtained from MM-PBSA. HIGHLIGHTSVirtual screening for new antitubercular medicines that targets NaMN adenylyltransferase.Ligand and structure-based pharmacophore modelling was employed in the study.The binding efficacy is validated by MM-PBSA calculations and molecular dynamics simulations.Compounds ZINC34698873 and CCG30319, demonstrating strong binding affinity to NaMN adenylyltransferase, show promise as candidates for antitubercular drugs. Virtual screening for new antitubercular medicines that targets NaMN adenylyltransferase. Ligand and structure-based pharmacophore modelling was employed in the study. The binding efficacy is validated by MM-PBSA calculations and molecular dynamics simulations. Compounds ZINC34698873 and CCG30319, demonstrating strong binding affinity to NaMN adenylyltransferase, show promise as candidates for antitubercular drugs.