A study of the interaction between HIV-1 protease and C 2-symmetric inhibitors by computational methods

The human immunodeficiency virus type 1 protease (HIV-1 PR) is a major target for the design of anti-AIDS (acquired immune deficiency syndrome) drugs. Some C2-symmetric inhibitors have been designed for the C2-symmetric binding pocket of HIV-1PR. The crystallographic structures reveal that the binding modes are not C2-symmetric for C2-symmetric inhibitors binding to PR. In this work, four molecular dynamics (MD) simulations were performed to investigate the binding modes between four C2-symmetric inhibitors (6 AD, 6AG, 6FD and 6FG) and PR, as well as the stabilities of these inhibitors in the binding pocket. Analysis of the hydrophobic surface of the binding pocket shows that it is necessary to add a polar group to the P1 (benzyl) and P2 (phenyl) groups of the inhibitor 6AD. Analysis of the hydrogen bonds formed between inhibitors and residues (Asp25/Asp25', Ile50/Ile50') indicates that the steric structures of the inhibitors are not suitable for the binding pocket. The two increased polar groups of trifluoromethyl and formamido meet the needs of the binding pocket for polar molecules. The inhibitor with both these groups (6FG) has stronger stability than the other three inhibitors, which have only one (6AG and 6FD) or none (6AD) of these groups. The ranking of binding free energies calculated by molecular mechanics-generalized born surface area (MM-GBSA) method agrees well with the experimental data. It is expected that this study will provide theoretical guidance for the design of anti-AIDS drugs targeting HIV-1PR.