Evolutionary analysis of HIV-1 protease inhibitors: Methods for design of inhibitors that evade resistance

Daniel Stoffler, Michel F. Sanner, Garrett M. Morris, Arthur J. Olson, David S. Goodsell

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Drug-resistant strains are rapidly selected during AIDS therapy because of the high rate of mutation in HIV. In this report, we present an evolutionary simulation method for analysis of viral mutation and its use for optimization of HIV-1 protease drugs to improve their robustness in the face of resistance mutation. We first present an analysis of the range of resistant mutants that produce viable viruses by using a volume-based viral fitness model. Then, we analyze how this range of mutant proteases allows development of resistance to an optimal inhibitor previously designed by computational coevolution techniques. Finally, we evaluate the resistance patterns of commercially available drugs, and we discuss how resistance might be overcome by optimizing the size of specific side-chains of these inhibitors.

Original languageEnglish (US)
Pages (from-to)63-74
Number of pages12
JournalProteins: Structure, Function and Genetics
Volume48
Issue number1
DOIs
StatePublished - Jul 1 2002

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology

Keywords

  • AIDS therapy
  • Coevolution
  • Computer-aided drug design
  • Drug resistance
  • HIV-1 protease

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