Comparative study of the unbinding process of some HTLV-1 protease inhibitors using unbiased molecular dynamics simulations

The HTLV-1 protease is one of the major antiviral targets to overwhelm this virus. Several research groups have developed protease inhibitors, but none has been successful. In this regard, developing new HTLV-1 protease inhibitors to fix the defects in previous inhibitors may overcome the lack of curative treatment for this oncovirus. Thus, we decided to study the unbinding pathways of the most potent (compound 10, PDB ID 4YDF, Ki = 15 nM) and one of the weakest (compound 9, PDB ID 4YDG, Ki = 7900 nM) protease inhibitors, which are very structurally similar. We conducted 12 successful short and long simulations (totaling 14.8 μs) to unbind the compounds from two monoprotonated (mp) forms of protease using the Supervised Molecular Dynamics (SuMD) without applying any biasing force. The results revealed that Asp32 or Asp32′ in the two forms of mp state similarly exert powerful effects on maintaining both potent and weak inhibitors in the binding pocket of HTLV-1 protease. In the potent inhibitor’s unbinding process, His66′ was a great supporter that was absent in the weak inhibitor’s unbinding pathway. In contrast, in the weak inhibitor’s unbinding process, Trp98/Trp98′ by pi-pi stacking interactions were unfavorable for the stability of the inhibitor in the binding site. In our opinion, these results will assist in designing more potent and effective inhibitors for the HTLV-1 protease.