3D-QSAR and molecular dynamics simulations of HIV-1 integrase and its complex with inhibitors

Abstract

Three dimensional quantitative structure activity relationship (3D-QSAR) techniques including CoMFA and CoMSIA were employed to determine the relationship between structural properties and biological activities of 11 and 10 diverse structural classes of HIV-1 integrase (IN) inhibitors against 3’-processing (89 compounds) and strand transfer (84 compounds) reactions, respectively. The single CoMFA model gave r2cv = 0.698 for 3’-processing activity and = 0.720 for strand transfer activity. The single CoMSIA model showed r2cv= 0.724 and = 0.656 for 3’-processing and strand transfer activities, respectively. Result analyses suggest that large substituents in the plane of the indole ring and the small bulky groups at the tetrazole ring of 5CITEP are required to increase the inhibitory potency of IN inhibitors. The groups of high electron density on ligand are also necessary for better interaction with the metal ion or the positive charge amino acids such as Lys156 and Lys159 in the active site of IN enzyme. To understand the structural and dynamical behaviors of protein-ligand complex, classical and hybrid quantum mechanical/molecular mechanism (QM/MM) molecular dynamics (MD) simulations were conducted for systems of HIV-1 IN complexed with 5CITEP (HIV-1 IN-5CITEP) and with its derivative, DKA (HIV-1 IN-DKA). The PM3 method was used to describe the QM region. Substantial differences between the two levels of calculations were observed at residues 116-119, residues 140-149, 4-helix, and the salt link interaction. In addition, the coordination of Mg2+ ion with ligand and water solvent in a near perfect octahedral complex was noticed in classical MD simulation. The QM/MM results between HIV-1 IN-5CITEP and HIV-1 IN-DKA were compared in order to explain the difference of inhibition mechanisms of the two inhibitors. The main findings of the differences between both systems are residues 116-119, the flexible loop residues 140-149, Mg2+ coordination, and salt link interaction. Mg2+ forms distorted octahedral complexes with 6 and 7 oxygen atoms as observed in HIV-1 IN-5CITEP and HIV-1 IN-DKA, respectively. The carboxylate moiety of DKA forms a stronger salt bridge interaction with Lys159 than the tetrazole ring of 5CITEP does. Moreover, the calculated binding free energy of HIV-1 IN-DKA is energetically more favorable than that of HIV-1 IN-5CITEP. The results supported the higher inhibitory potency of DKA in comparison with 5CITEP.