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

<div><p>Multidrug resistance capacity of <i>Mycobacterium tuberculosis</i> demands urgent need for developing new antitubercular drugs. The present work is on <i>M. tuberculosis-</i>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 <i>M. tuberculosis-</i>MbtA 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 (<i>R</i>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 (<i>R</i>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.</p><p>An animated interactive 3D complement (I3DC) is available in Proteopedia at <a href="http://proteopedia.org/w/Journal:JBSD:33" target="_blank">http://proteopedia.org/w/Journal:JBSD:33</a></p></div

Computational screening for new inhibitors of <i>M. tuberculosis</i> mycolyltransferases antigen 85 group of proteins as potential drug targets

<div><p>The group of antigen 85 proteins of <i>Mycobacterium tuberculosis</i> is responsible for converting trehalose monomycolate to trehalose dimycolate, which contributes to cell wall stability. Here, we have used a serial enrichment approach to identify new potential inhibitors by searching the libraries of compounds using both 2D atom pair descriptors and binary fingerprints followed by molecular docking. Three different docking softwares AutoDock, GOLD, and LigandFit were used for docking calculations. In addition, we applied the criteria of selecting compounds with binding efficiency close to the starting known inhibitor and showing potential to form hydrogen bonds with the active site amino acid residues. The starting inhibitor was ethyl-3-phenoxybenzyl-butylphosphonate, which had IC₅₀ value of 2.0 μM in mycolyltransferase inhibition assay. Our search from more than 34 million compounds from public libraries yielded 49 compounds. Subsequently, selection was restricted to compounds conforming to the Lipinski rule of five and exhibiting hydrogen bonding to any of the amino acid residues in the active site pocket of all three proteins of antigen 85A, 85B, and 85C. Finally, we selected those ligands which were ranked top in the table with other known decoys in all the docking results. The compound NIH415032 from tuberculosis antimicrobial acquisition and coordinating facility was further examined using molecular dynamics simulations for 10 ns. These results showed that the binding is stable, although some of the hydrogen bond atom pairs varied through the course of simulation. The NIH415032 has antitubercular properties with IC₉₀ at 20 μg/ml (53.023 μM). These results will be helpful to the medicinal chemists for developing new antitubercular molecules for testing.</p> </div