Molecular docking, validation, dynamic simulation and pharmacokinetic prediction of natural compounds against Mycobacterium tuberculosis Beta-lactamase BlaC

Tuberculosis, caused by Mycobacterium tuberculosis ranks second globally in terms of infectious disease-related deaths, after HIV. The resistance of M. tuberculosis to existing beta-lactam antibiotics is primarily due to chromosomally encoded gene blaC, which can hydrolyse predominantly available beta-lactam antibiotics. Despite the available beta-lactamase inhibitors with beta-lactam ring such as clavulanate, being efficacious, they lead the bacteria to develop an inhibitor escape mechanism. In contrast, the natural product inhibitors without beta-lactam ring that might resist bacterial escape mechanisms have the additional advantage of fewer side effects, higher bioavailability, and better bioremediation towards environmental sustainability. This study identifies novel natural inhibitors against BlaC, from the Natural Products Atlas database of PubChem and ZINC comprising 10,000 compounds using molecular docking and Molecular Dynamics (MD) simulations. The virtual screening and docking experiments demonstrated that the top 10 compounds exhibited favourable docking scores in the range of -7.59 to -9.63 kcal/mol compared to the reference molecule, Doripenem (-7.35 kcal/mol). Following targeted docking and ADMET analysis, three lead compounds Lecanorafuran A, Tryptoquivaline K, and Deacetylisowortmin A were selected for MD simulations for a period of 100 ns to evaluate the stability of the protein-ligand complexes. Based on Root Mean Square Deviation, Root Mean Square Fluctuation, Radius of gyration and Solvent Accessible Surface Area, PCA, and FEL analysis, it was found that Tryptoquivaline K exhibited consistent stability throughout the simulation. Additionally, Molecular Mechanics/Poisson-Boltzmann Surface Area (MMPBSA) analysis was conducted to assess the binding affinity of the complex. All these analyses validate that the natural compound Tryptoquivaline K exhibits potential as a promising BlaC inhibitor but warrants further validation through experimental studies in this aspect.