Modeling of the Inhibition of Retroviral Integrases by Styrylquinoline Derivatives

• Published in: Journal of medicinal chemistry Vol. 43; no. 10; pp. 1949 - 1957
• Main Authors: Ouali, Mohammed, Laboulais, Cyril, Leh, Hervé, Gill, David, Desmaële, Didier, Mekouar, Khalid, Zouhiri, Fatima, d'Angelo, Jean, Auclair, Christian, Mouscadet, Jean-François, Le Bret, Marc
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 18.05.2000
• Subjects: AIDS/HIV; Algorithms; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Avian Sarcoma Viruses - enzymology; Binding Sites; Biological and medical sciences; DNA - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; HIV Integrase - chemistry; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - metabolism; HIV-1 - enzymology; Integrases - metabolism; Magnesium - metabolism; Medical sciences; Models, Molecular; Molecular Conformation; Molecular Structure; Pharmacology. Drug treatments; Quinolines - chemistry; Quinolines - metabolism; Recombinant Proteins - metabolism; Static Electricity; Structure-Activity Relationship; Thermodynamics; Enzyme; Nitrogen heterocycle; Ab initio method; Transferases; Retroviridae; Enzyme inhibitor; Quinoline derivatives; Rous sarcoma virus; Lentivirus; Modeling; Virus; Nucleotidyltransferases; Avian sarcoma virus; Structure activity relation; Carboxylic acid; Binding energy; Molecular model; Bicyclic compound; Phenols; Antiviral; Avian type C retrovirus; Aromatic compound; Human immunodeficiency virus; Electrostatic model
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9911581

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 Mg2+ dication. Additional quantum chemistry computations show that there is no direct correlation between the binding energy of the drugs with the Mg2+ dication and their in vitro inhibitory effect. The designed method is a leading way for identification of potent integrase inhibitors using in silico experiments.