An insight into the binding mechanism of Viprinin and its morpholine and piperidine derivatives with HIV-1 Vpr: molecular dynamics simulation, principal component analysis and binding free energy calculation study.

HIV-1 Vpr is an accessory protein responsible for a plethora of functions inside the host cell to promote viral pathogenesis. One of the major functions of Vpr is the G2 cell cycle arrest. Among several small molecule inhibitors, Viprinin, a coumarin derivative, has been shown to specifically inhibit the G2 cell cycle arrest activity of Vpr thus making it an excellent choice for a lead molecule to design antiretroviral drug. But the exact mechanism of binding of the Viprinin and its two potent derivatives with Vpr is still not understood. In this study with combined molecular docking, molecular dynamics simulation, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method, Principal component analysis and Umbrella sampling simulation, we have explored the binding mechanism of Viprinin and its two derivatives with Vpr. MM-PBSA and Umbrella sampling calculations suggest that Viprinin and ViprininD1 have higher binding energy than ViprininD2. Molecular dynamics simulation shows that the ligands are not very stable inside the initial binding pocket and various hydrophobic interactions are responsible to hold the ligands with Vpr. Vpr backbone Principle Component Analysis (PCA) shows various unique essential motions of Vpr bound with Viprinin and its two derivatives. This study may give detailed insight of the mode of binding of the specified compounds at atomic scale and provide valuable information about the possibility of using these compounds as a potent Vpr inhibitor. Communicated by Ramaswamy H. Sarma.