Modified bis‐tetrahydrofuran inhibitors toward improved binding to HIV‐1 proteases

Abstract

AbstractHIV treatment includes inhibiting HIV‐1 protease which is responsible for viral maturation. However, HIV‐1 protease responds to drug treatment by mutation making the protease‐resistant to inhibitors. In this study, binding interactions between bis‐tetrahydrofuran‐derived (bis‐THF) inhibitors and HIV‐1 protease were described by molecular docking. We characterized the binding energies and all the amino acids present during the binding of the bis‐THF derivatives to the wild type HIV‐1 protease and several mutant HIV‐1 proteases. We found that the modifications to the structure of darunavir helped improve its binding to the wild‐type protease. Also, these structures were found to interact with the mutant HIV‐1 proteases better than darunavir. Results showed that compound 4 had the highest binding energy to the wild‐type HIV‐1 protease and the V654/84 mutant, while compound 5 was found to interact greatly with cyclic urea‐based inhibitor‐resistant proteases and the multi‐protease inhibitor‐resistant HIV‐1 protease. The results may help explain how structural modifications to bis‐tetrahydrofuran inhibitors affect their response to wild‐type and resistant HIV‐1 proteases. Furthermore, this study is the first demonstration of the differences in the amino acids interacting with protease inhibitors for wild‐type and mutated HIV‐1 proteases and may help in the design of bis‐THF derivatives as HIV‐1 protease inhibitors.