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

College

College of Science

Department/Unit

Chemistry

Document Type

Article

Source Title

Vietnam Journal of Chemistry

Volume

59

Issue

5

First Page

563

Last Page

579

Publication Date

2021

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.

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Digitial Object Identifier (DOI)

10.1002/vjch.202000179

Keywords

HIV (Viruses); Protease inhibitors

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