Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by Supervised Molecular Dynamics simulation

Abstract

Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing SuMD method, we reconstructed the unbinding pathways of indinavir from HIV and HTLV-1 proteases in order to compare and to understand the mechanism of the unbinding, and also to discover the reasons for the lack of inhibitory activity of indinavir against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases in which the RMSD values of indinavir reached over 4 nm. Also, we found that the mobility and the fluctuations of the flap region is higher in the HTLV-1 protease which makes the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98' and Phe67/Phe67' in the HTLV-1 protease can make strong pi-Stacking interactions with indinavir in the unbinding pathway which are unfavorable for the stability of indinavir in the active site. The details found in this study can make a good explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can be a great assist for designing more effective and more selective inhibitors for the HTLV-1 protease.