To discuss the conformational change and the recognition mechanism of hydroxy isoindol ketone derivatives with HIV-1 integrase, fifty-eight hydroxy isoindol ketone derivatives were docked to the integrase using AutoDock program. Molecular dynamics simulation with 16 ns was carried out for the two complex modes, respectively, in which the corresponding small molecules exhibited strong inhibition ability. Main force acting on the association of small molecules with integrase was explored based on the docking complex model. After analyzing the hydrogen-bond and conformational changes, it was found that the hydrogen-bond between N155 and D64 was the key factor maintaining the DDE motif stability. Furthermore, the hydrophobic interactions between the loop region where Y143 located and the hydroxy isoindol ketone derivatives were found to play an important role for their recognition.

Faldaprevir analogue molecule (FAM) has been reported to effectively inhibit the catalytic activity of HCV NS3/4A protease, making it a potential lead compound against HCV. A series of HCV NS3/4A protease crystal structures were analyzed by bioinformatics methods, and the FAM-HCV NS3/4A protease crystal structure was chosen for this study. A 20.4 ns molecular dynamics simulation of the complex consists of HCV NS3/4A protease and FAM was conducted. The key amino acid residues for interaction and the binding driving force for the molecular recognition between the protease and FAM were identified from the hydrogen bonds and binding free energy analyses. With the driving force of hydrogen bonds and van der Waals, FAM specifically bind to the active pocket of HCV NS3/4A protease, including V130-S137, F152-D166, D77-D79 and V55, which agreed with the experimental data. The effect of R155K, D168E/V and V170T site-directed mutagenesis on FAM molecular recognition was analyzed for their effect on drug resistance, which provided the possible molecular explanation of FAM resistance. Finally, the system conformational change was explored by using free energy landscape and conformational cluster. The result showed four kinds of dominant conformation, which provides theoretical basis for subsequent design of Faldaprevir analogue inhibitors based on the structure of HCV NS3/4A protease.
Antiviral Agents ; chemistry ; Carrier Proteins ; chemistry ; Drug Resistance, Viral ; Endopeptidases ; Hepacivirus ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Oligopeptides ; chemistry ; Protease Inhibitors ; chemistry ; Serine Proteases ; Thiazoles ; chemistry ; Viral Nonstructural Proteins ; chemistry