title: Modeling of the inhibition of retroviral integrases by styrylquinoline derivatives.
abstract: Styrylquinoline derivatives, known to be potent inhibitors of HIV-1 integrase, have been experimentally tested for their inhibitory effect on the disintegration reaction catalyzed by catalytic cores of HIV-1 and Rous sarcoma virus (RSV) integrases. A modified docking protocol, consisting of coupling a grid search method with full energy minimization, has been specially designed to study the interaction between the inhibitors and the integrases. The inhibitors consist of two moieties that have hydroxyl and/or carboxyl substituents: the first moiety is either benzene, phenol, catechol, resorcinol, or salicycilic acid; the hydroxyl substituents on the second (quinoline) moiety may be in the keto or in the enol forms. Several tautomeric forms of the drugs have been docked to the crystallographic structure of the RSV catalytic core. The computed binding energy of the keto forms correlates best with the measured inhibitory effect. The docking procedure shows that the inhibitors bind closely to the crystallographic catalytic Mg(2+) dication. Additional quantum chemistry computations show that there is no direct correlation between the binding energy of the drugs with the Mg(2+) dication and their in vitro inhibitory effect. The designed method is a leading way for identification of potent integrase inhibitors using in silico experiments.
authors.affiliation: Laboratoire de Physicochimie et de Pharmacologie des Macromolécules Biologiques, CNRS UMR 8532, LBPA, Ecole Normale Supérieure de Cachan, 61 avenue du Président Wilson, 94235 Cachan, France.
authors.forename: M
authors.initials: M
authors.lastname: Ouali
authors.forename: C
authors.initials: C
authors.lastname: Laboulais
authors.forename: H
authors.initials: H
authors.lastname: Leh
authors.forename: D
authors.initials: D
authors.lastname: Gill
authors.forename: D
authors.initials: D
authors.lastname: Desmaële
authors.forename: K
authors.initials: K
authors.lastname: Mekouar
authors.forename: F
authors.initials: F
authors.lastname: Zouhiri
authors.forename: J
authors.initials: J
authors.lastname: d'Angelo
authors.forename: C
authors.initials: C
authors.lastname: Auclair
authors.forename: J F
authors.initials: JF
authors.lastname: Mouscadet
authors.forename: M
authors.initials: M
authors.lastname: Le Bret
mesh_terms: D000465:Algorithms; D001358:Avian Sarcoma Viruses / Q000201:enzymology; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D019426:Integrases / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D019428:HIV Integrase Inhibitors; D011804:Quinolines; D011994:Recombinant Proteins; D004247:DNA; D019427:HIV Integrase; D019426:Integrases; D008274:Magnesium