Modeling of the inhibition of retroviral integrases by styrylquinoline derivatives

Styrylquinoline derivatives, known to be potent inhibitors of HTV-1 integra se, have been experimentally tested for their inhibitory effect on the disi ntegration 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 des igned to study the interaction between the inhibitors and the integrases. T he inhibitors consist of two moieties that have hydroxyl and/or carboxyl su bstituents: the first moiety is either benzene, phenol, catechol, resorcino l, or salicycilic acid; the hydroxyl substituents on the second (quinoline) moiety may be in the keto or in the enol forms. Several tautomeric forms o f the drugs have been docked to the crystallographic structure of the RSV c atalytic core. The computed binding energy of the keto forms correlates bes t with the measured inhibitory effect. The docking procedure shows that the inhibitors bind closely to the crystallographic catalytic Mg2+ dication. A dditional quantum chemistry computations show that there is no direct corre lation between the binding energy of the drugs with the Mg2+ dication and t heir in, vitro inhibitory effect. The designed method is a leading way for identification of potent integrase inhibitors using in silico experiments.