Title : Exploring the phytochemical based inhibition of PonA1 from Mycobacterium tuberculosis by molecular docking, dynamic simulation and ADMET studies
Abstract:
Objective: To perform molecular docking of plant-based bioactive compounds against a class of penicillin-binding protein PonA1 from Mycobacterium tuberculosis causing tuberculosis in humans. This study also authenticated the stable protein-ligand binding by molecular dynamic simulation.
Methods: The 3D structures of Withania somnifera (in Bengali Ashawagandha) phytochemicals, such as viscosalactone B, withaferin A and withanolide A, were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/), and were used as the ligands. The crystal structure of PonA1 (from Mycobacterium tuberculosis) was selected as target, and was downloaded from RCSB Protein Data Bank (https://www.rcsb.org/), in 3D form. We have docked the phytochemical ligands to MtPonA1, and the protein-ligand interactions were analysed. Kanamycin was used as the control. The pharmacokinetics profile of the phytochemical ligands (viscosalactone B, withaferin A and withanolide A) were predicted in silico, and the structural authenticity of MtPonA1 was determined through Ramachandran plot analysis.
Results: The docking analysis showed the highest binding affinity of withanolide A (binding energy −10.7 kcal/mol), followed by viscosalactone B (binding energy −9.2 kcal/mol) and withaferin A (−9.0 kcal/mol), against MtPonA1. The binding affinity of withanolide A to MtPonA1 was higher compared to the 2 other bioactive compounds, and hence the 'MtPonA1- withanolide A' complex and the free components of the docked complex (ligand and protein alone) were subjected to MDS, authenticating their stable binding, due to low binding free energy (−110.17 kJ/mol) with RMS deviation 0.15 nm and maximum RMS fluctuation 0.055 nm. Pharmacokinetics prediction revealed the acceptability of the ligands as drug-like compounds.
Conclusion: This in silico study suggests the usefulness of Withania somnifera derived bioactive chemical compounds as suitable leads to manage Mycobacterium tuberculosis infection causing deadly tuberculosis in humans.
