Rational design of potent non-nucleoside inhibitors of HIV-1 reverse transcriptase

J Med Chem. 2012 Dec 13;55(23):10601-9. doi: 10.1021/jm301294g. Epub 2012 Nov 26.

Abstract

A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound 43 that exhibits remarkable antiviral activity (EC50<1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.

MeSH terms

  • Crystallography, X-Ray
  • Drug Design*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • Reverse Transcriptase Inhibitors
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase

Associated data

  • PDB/2YNF
  • PDB/2YNG
  • PDB/2YNH
  • PDB/2YNI