Higher desolvation energy reduces molecular recognition in multi-drug resistant HIV-1 protease

Yong Wang, Tamaria G. Dewdney, Zhigang Liu, Samuel J. Reiter, Joseph S. Brunzelle, Iulia A. Kovari, Ladislau C. Kovari

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1'F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

Original languageEnglish (US)
Pages (from-to)81-93
Number of pages13
JournalBiology
Volume1
Issue number1
DOIs
StatePublished - May 31 2012

Keywords

  • Desolvation energy
  • Multi-drug resistant HIV-1 protease
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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