Additivity in the analysis and design of HIV protease inhibitors

Robert N. Jorissen, G. S. Kiran Kumar Reddy, Akbar Ali, Michael D. Altman, Sripriya Chellappan, Saima G. Anjum, Bruce Tidor, Celia A. Schiffer, Tariq M. Rana, Michael K. Gilson

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridge-regression methods were found to yield statistically similar results. The additivity approach was also compared with standard molecular descriptor-based QSAR; the latter was not found to provide superior predictions. Crystallographic studies of HIV protease-inhibitor complexes help explain the perhaps surprisingly high degree of substituent additivity in this system, and allow some of the additivity coefficients to be rationalized on a structural basis.

Original languageEnglish
Pages (from-to)737-754
Number of pages18
JournalJournal of medicinal chemistry
Volume52
Issue number3
DOIs
Publication statusPublished or Issued - 12 Feb 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this