title: A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910.
abstract: Diarylquinolines (DARQs) are a new class of potent inhibitors of the ATPase of Mycobacterium tuberculosis. We have created a homology model of a binding site for this class of compounds located on the contact area of the a-subunit (gene atpB) and c-subunits (gene atpE) of Mycobacterium tuberculosis ATPase. The binding pocket that was identified from the analysis of the homology model is formed by 4 helices of three c-subunits and 2 helices of the a-subunit. The lead compound of the DARQ series, R207910, was docked into the pocket using a simulated annealing, multiple conformer, docking algorithm. Different stereoisomers were treated separately. The best docking pose for each stereoisomer was optimized by molecular dynamics simulation on the 5300 atoms of the binding region and ligand. The interaction energies in the computed complexes enable us to rank the different stereoisomers in order of interaction strength with the ATPase binding pockets. We propose that the activity of R207910 against Mycobacterium tuberculosis is based on interference of the compound with the escapement geometry of the proton transfer chain. Upon binding the compound mimics the conserved Arg-186 residue of the a-subunit and interacts in its place with the conserved acidic residue Glu-61 of the c-subunit. This mode of action is corroborated by the good agreement between the computed interaction energies and the observed pattern of stereo-specificity in the model of the binding region.
authors: MolMo Services BVBA, Campus Blairon 424, B2300 Turnhout, Belgium. marc@molmo.be
authors: Marc R
authors: MR
authors: de Jonge
authors: Luc H M
authors: LH
authors: Koymans
authors: Jérôme E G
authors: JE
authors: Guillemont
authors: Anil
authors: A
authors: Koul
authors: Koen
authors: K
authors: Andries
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D064687:Diarylquinolines; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005277:Fenfluramine; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D011485:Protein Binding; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D064687:Diarylquinolines; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D011804:Quinolines; D005277:Fenfluramine; C493870:bedaquiline; D000251:Adenosine Triphosphatases