Study on the Resistance and the Binding Mode of HIV-1 Integrase to NSC158393

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding modes of the wild type IN core domain and the W132G mutant with the hydroxycoumarin compound NSC158393 were investigated by using the "relaxed complex" molecular docking approach and molecular dynamics (MD) simulation. Based on results of molecular docking experiment, NSC15893 binds the backbone of the 128-136 peptide adjacent to the dimer interface. The W132G substitution slightly distort the binding pocket of NSC158393, thus inducing the change of the binding mode. From the comparative analysis of the MD trajectories of the wild type IN and the IN-NSC158393 complex, it is found that the binding of NSC15893 diminishes the mobility of the function loop of IN. All the above results are consistent with experiments, providing us some helpful information for understanding the mechanism of the coumarin-based inhibitors.