title: Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors.
abstract: We extended the previously described dynamic pharmacophore model studies of HIV-1 integrase (IN) by considering more key residues in the active site, including Mg2+. First, we applied a Monte Carlo sampling method to map the complementary features of the IN binding surface. Two types of dynamic pharmacophore models were generated. One considers Mg2+ as part of the IN and therefore as an excluded volume, and the other treats Mg2+ as a positively charged feature, representing a new type of pharmacophore model aimed to identify compounds potentially preventing Mg2+ binding. Second, we validated the models with 385 known active (IC50 < 20 microM) and 235 (IC50 > 100 microM) inactive IN inhibitors. Third, we used the derived models to screen our small molecule database. Twenty-two structurally novel compounds were tested in an in vitro assay specific for IN, and two of them showed IC50 < or = 10 microM for strand transfer reaction.
authors.affiliation: Department of Chemical Engineering, University of Houston, Houston, Texas 77204, USA.
authors.forename: Jinxia
authors.initials: J
authors.lastname: Deng
authors.forename: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: James M
authors.initials: JM
authors.lastname: Briggs
mesh_terms: D000465:Algorithms; D000880:Anthraquinones / Q000737:chemistry; D001665:Binding Sites; D002413:Cations, Divalent / Q000737:chemistry; D016208:Databases, Factual; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D008274:Magnesium / Q000737:chemistry; D008958:Models, Molecular; D009010:Monte Carlo Method; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry
chemical_list: D000880:Anthraquinones; D002413:Cations, Divalent; D019428:HIV Integrase Inhibitors; D011720:Pyrazoles; D019427:HIV Integrase; D008274:Magnesium; C046659:piroxantrone