Probing the structure of Mycobacterium tuberculosis MbtA: model validation using molecular dynamics simulations and docking studies

Multidrug resistance capacity of Mycobacterium tuberculosis demands urgent need for developing new antitubercular drugs. The present work is on M. tuberculosis-MbtA, an enzyme involved in the biosynthesis of siderophores, having a critical role in bacterial growth and virulence. The molecular models of both holo and apo forms of M. tuberculosisMbtA have been constructed and validated. A docking study with a series of 42 5'-O-[ N-(salicyl) sulfamoyl] adenosine derivatives, using GOLD software, revealed significant correlation (R-2 = 0.8611) between Goldscore and the reported binding affinity data. Further, binding energies of the docked poses were calculated and compared with the observed binding affinities (R-2 = 0.901). All-atom molecular dynamics simulation was performed for apo form, holo form without ligand and holo form with ligands. The holo form without ligand on molecular dynamics simulation for 20 ns converged to the apo form and the apo form upon induced fit docking of the natural substrate, 2,3-dihydroxybenzoic acid-adenylate, yielded the holo structure. The molecular dynamics simulation of the holo form with ligands across the time period of 20 ns provided with the insights into ligand-receptor interactions for inhibition of the enzyme. A thorough study involving interaction energy calculation between the ligands and the active site residues of MbtA model identified the key residues implicated in ligand binding. The holo model was capable to differentiate active compounds from decoys. In the absence of experimental structure of MbtA, the homology models together with the insights gained from this study will promote the rational design of potent and selective MbtA inhibitors as antitubercular therapeutics.