Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA-approved inhibitors: MD study.

HIV-1 protease (HIV PR) is considered as one of the most attractive targets for the treatment of HIV and the impact of flap dynamics of HIV PR on the binding affinities of protease inhibitors (PIs) is a crucial ongoing research field. Recently, our research group evaluated the binding affinities of different FDA approved PIs against the South African HIV-1 subtype C (C-SA) protease (PR). The CSA-HIV PR displayed weaker binding affinity for most of the clinical PIs compared to HIV-1 B subtype for West and Central Europe, the Americas. In the current work, the flap dynamics of four different systems of HIV-1 C-SA PR complexed to FDA approved second generation PIs and its impact on binding was explored over the molecular dynamic trajectories. It was observed that the interactions of the selected drugs with the binding site residues of the protease may not be the major contributor for affinity towards PIs. Various post-MD analyses were performed, also entropic contributions, solvation free energies and hydrophobic core formation interactions were studied to assess how the flap dynamics of C-SA PR which is affected by such factors. From these contributions, large van der Waals interactions and low solvation free energies were found to be major factors for the higher activity of ATV against C-SA HIV PR. Furthermore, a comparatively stable hydrophobic core may be responsible for higher stability of the PR flaps of the ATV complex. The outcome of this study provides significant guidance to how the flap dynamics of C-SA PR is affected by various factors as a result of the binding affinity of various protease inhibitors. It will also assist with the design of potent inhibitors against C-SA HIV PR that apart from binding in the active site of PR can interacts with the flaps to prevent opening of the flaps resulting in inactivation of the protease.
(© 2018 John Wiley & Sons A/S.)