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

Abstract

HIV 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.