Coevolution and subsite decomposition for the design of resistance-evading HIV-1 protease inhibitors

Christopher D. Rosin, Richard K. Belew, Wynn L. Walker, Garrett M. Morris, Arthur J. Olson, David S. Goodsell

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Drug resistance sharply limits the effectiveness of human immunodeficiency virus (HIV) protease inhibitors in acquired immunodeficiency syndrome therapy. In previous work, we presented methods for design of resistance-evading inhibitors using a computational coevolution technique. Here, we report subsite decomposition experiments that examine the relative importance and roles of each subsite in HIV protease, and the constraints on robust inhibitor design that are imposed by possible resistance mutations in each subsite. The results identify several structural features of robust resistance-evading inhibitors for use in drug design, and show their basis in the constraints imposed by the range of allowable mutation in the protease. In particular, the results identify the P3 and P3' sites as being particularly sensitive to protease mutation: inhibitors designed to fill the S3 and S3' sites of the wild-type protease will be susceptible to viral resistance, but inhibitors with side-chains smaller than a phenylalanine residue at P3 and P3', preferably medium-sized amino acids in the range from valine to leucine and isoleucine residues, will be more robust in the face of protease resistance mutation.

Original languageEnglish (US)
Pages (from-to)77-92
Number of pages16
JournalJournal of molecular biology
Issue number1
StatePublished - Mar 19 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology


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


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