Validation of a model for the complex of HIV-1 reverse transcriptase with nonnucleoside inhibitor TMC125

J Am Chem Soc. 2003 May 21;125(20):6016-7. doi: 10.1021/ja034308c.

Abstract

The structure for the complex of nonnucleoside inhibitor TMC125 and HIV-1 reverse transcriptase has been determined and validated through computation of resistance profiles using Monte Carlo/free-energy perturbation calculations. The good quantitative agreement between the computed and experimental anti-HIV activities for TMC125, nevirapine, and efavirenz with wild-type RT and four common mutants (L100I, K103N, Y181C, and Y188L) confirms the correctness of the predicted structure and provides insights into the improved potency of this novel NNRTI. The blue shading in the figure indicates basic residues.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • Models, Molecular
  • Mutagenesis
  • Nitriles
  • Pyridazines*
  • Pyrimidines
  • Reproducibility of Results
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology
  • Thermodynamics

Substances

  • Anti-HIV Agents
  • Nitriles
  • Pyridazines
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • etravirine
  • HIV Reverse Transcriptase