title: Conformational analysis of TMC114, a novel HIV-1 protease inhibitor.
abstract: TMC114, a potent novel HIV-1 protease inhibitor, remains active against a broad spectrum of mutant viruses. In order to bind to a variety of mutants, the compound needs to make strong, preferably backbone, interactions and have enough conformational flexibility to adapt to the changing geometry of the active site. The conformational analysis of TMC114 in the gas phase yielded 43 conformers in which five types of intramolecular H-bond interactions could be observed. All 43 conformers were subject to both rigid and flexible ligand docking in the wild-type and a triple mutant (L63P/V82T/I84V) of HIV-1 protease. The largest binding energy was calculated for the conformations that are close to the conformation observed in the X-ray complexes of TMC114 and HIV-1 protease.
authors.affiliation: Department of Chemistry, University of Antwerp, Drie Eiken Campus, B-2610 Antwerp, Belgium.
authors.forename: Kanda
authors.initials: K
authors.lastname: Nivesanond
authors.forename: Anik
authors.initials: A
authors.lastname: Peeters
authors.forename: Dirk
authors.initials: D
authors.lastname: Lamoen
authors.forename: Christian
authors.initials: C
authors.lastname: Van Alsenoy
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D000069454:Darunavir; D005740:Gases / Q000737:chemistry; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D005740:Gases; D017320:HIV Protease Inhibitors; D008024:Ligands; D013449:Sulfonamides; D014867:Water; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir