Design, synthesis, evaluation, and crystallographic-based structural studies of HIV-1 protease inhibitors with reduced response to the V82A mutation

J Med Chem. 2008 Feb 28;51(4):852-60. doi: 10.1021/jm701170f. Epub 2008 Jan 24.

Abstract

In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C2-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1'. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of the Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Cyclohexanes / chemical synthesis*
  • Cyclohexanes / chemistry
  • Drug Design
  • Drug Resistance, Viral
  • HIV Protease / chemistry*
  • HIV Protease / genetics
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV-1 / enzymology*
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Protein Binding
  • Stereoisomerism
  • Thermodynamics

Substances

  • Cyclohexanes
  • HIV Protease Inhibitors
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1

Associated data

  • PDB/2FLE