HIV-1 protease continues to be a major target for therapy against AIDS. Although there are ten FDA approved drugs available, long term use of these drugs elicit drug resistant mutations leading to major challenges in therapy. Recently there have been reports of a new inhibitor, TMC310911 (TMC) that has shown significant activity against a wide spectrum of HIV clinical isolates that are resistant to even darunavir (DRV), the best HIV-1 protease drug so far. However the mechanism of action of TMC is unknown. In this work, we have employed all-atom molecular dynamics simulation to understand how TMC can be a potential drug candidate against mulidrug-resistant protease variants. Our results suggest that TMC has a dual mode of action. It acts as a conventional peptidomimetic inhibitor as well as a dimerisation inhibitor. It can bind to the active site cavity of dimeric protease in an extended conformation similar to the available crystal structure pose. In parallel, it can also bind to the monomeric protease and block the dimerisation interface of variant monomers. The detailed mechanism of action of TMC and the underlined mode of interaction could pave way for designing other potential HIV-1 protease inhibitors. © 2019 Elsevier B.V.