Molecular Dynamics Study Of The Novel Inhibitor For HIV-1Protease

Acquired Immune Deficiency Syndrome (AIDS) is caused by Human ImmunodeficiencyVirus (HIV) which can spread across different species. HIV belongs to lentivirus subfamily ofretrovirus, and it can be divided into two types, HIV-I and HIV-II. There are many subtypesunder above two types, and HIV-I is the main reason for the infection of AIDS in humans. HIV-1protease is an important enzyme for viral replication, And HIV-1protease inhibitor which as animportant component of highly active antiretroviral therapy (HARR) plays an necessary role forthe survival of people with AIDS. FDA (Food and Drug Administration) currently have approvedten HIV-1protease inhibitors which are targeted at the active site. However, HIV has evolveddrug resistance variation of the existing drug, which make more than10%of new HIV infectionPatients be infected in the United States, so the design of new inhibitors for HIV-1proteasebecomes extremely urgent. A. Perryman et al recently found that there are two novel binding sites(allosteric binding sites) on the protease surface beside the active site. The two allosteric bindingsites are Exo site and the Outside/top of flap site, and in the two sites binding two compounds,2-methylcyclohexanol and6-indoleformicacid, which can stabilize the conformation of theactive site inhibitor, although not yet demonstrated inhibition now but it can be a starting pointfor the development of resistant HIV drug. This discovery laid the basis for the development ofnovel anti-HIV drugs, the new drugs can be designed along this route to enhance the efficacy ofexisting therapies, cure drug-resistant type, slow down the evolution of viral resistance.Molecular Dynamics (MD) simulation, which provides the methodology for detailedmicroscopic modeling on the atomic scale, is a powerful and widely used tool in chemistry,biomedical, materials science and other fields. By numerically solving the equations of motionwe can study time-dependent processes of detailed atomic motions, thermodynamic properties ofthe system. And it is a powerful tool to understand protein-ligand complexes.Graphics process uni（tGPU） was originally designed to render computer images, but GPUhas become increasingly widely used in scientific computing, engineering, finance and otherfields. And NVIDIA corporation’GPU which base on Compute unified device architecture（CUDA） which is a parallel computing architecture have been accelerating Amber moleculardynamics simulation program. Computing is now evolving from "central processing" on theCPU to "co-processing" on the CPU and GPU. The GPU which has hundreds of processor cores in the chip can solve the complex time-consuming molecular dynamics calculations with morethan one hundred times speed than traditional methods using the large-scale parallelcommunications and collaboration.In this study, We performed200nanosecond long time scale molecular dynamics simulationfor the allosteric inhibitor system and active site inhibitor system of HIV-1protease respectively,employed the recently developed ff12SB force field on NVIDIA CUDA GPU. We found anotherbinding site except for Exo-site of2-methylcyclohexanol, and analyzed the binding process, andboth systems’bind free energy of active site inhibitor TL-3with HIV-1protease were calculatedusing MM-PBSA method in different binding conditions.2-methylcyclohexanol’ hydroxyl groupand attachment site exists hydrogen bonds, the methylcyclohexyl group and the attachment sitealso exits hydrophobic interaction. Fragment2-methylcyclohexanol, binds in the Exo site,stabilizes the inhibited conformation of the target. And free energy of inhibitor TL-3binding toprotease is-82.41kcal/mol (4DX binding at Exo-site) and-84.93kcal/mol (4DX binding atBexo-site) in allosteric inhibitor system, and-68.47kcal/mol in active site inhibitor system.These results might help to gain a better insight into the dynamics of HIV-1PR, which mayprovide important guidelines for the design of novel potent inhibitors.