AbstractMycobacterium tuberculosis, the leading bacterial killer disease worldwide, causes Human tuberculosis (TB). Due to the growing problem of drug resistant Mycobacterium tuberculosis strains, new anti-TB drugs are urgently needed. Natural sources such as plant extracts have long played an important role in tuberculosis management and can be used as a template to design new drugs. A wide screening of natural sources is time consuming but the process can be significantly sped up using molecular docking. In this study, we used a molecular docking approach to investigate the interactions between selected natural constituents and three proteins MtPanK, MtDprE1 and MtKasA involved in the physiological functions of Mycobacterium tuberculosis which are necessary for the bacteria to survive and cause disease. The molecular docking score, a score that accounts for the binding affinity between a ligand and a target protein, for each protein was calculated against 150 chemical constituents of different classes to estimate the binding free energy. The docking scores represent the binding free energy. The best docking scores indicates the highest ligand protein binding which is indicated by the lowest energy value. Among the natural constituents, Shermilamine B showed a docking score of - 8.5kcal/mol, Brachystamide B showed a docking score of −8.6 kcal/mol with MtPanK, Monoamphilectine A showed a score of −9.8kcal/mol with MtDprE1.These three compounds showed docking scores which were superior to the control inhibitors and represent the opportunity of in vitro biological evaluation and anti-TB drug design. Consequently, all these compounds belonged to the alkaloid class. Specific interactions were studied to further understand the nature of intermolecular bonds between the most active ligands and the protein binding site residues which proved that among the constituents monoamphilectine A and Shermilamine B show more promise as Anti-TB drugs. Furthermore, the ADMET properties of these compounds or ligands showed that they have no corrosive or carcinogenic parameters.Graphical Abstract
Absolute Protein Binding Free Energy Simulations for Ligands with Multiple Poses, a Thermodynamic Path That Avoids Exhaustive Enumeration of the Poses
