A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 to identify new inhibitors of gp120-CD4 protein-protein interactions

Bioorg Med Chem Lett. 2009 Nov 1;19(21):6087-91. doi: 10.1016/j.bmcl.2009.09.029. Epub 2009 Sep 13.

Abstract

A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 was built and used to identify new hits able to inhibit gp120-CD4 protein-protein interactions. Two compounds showed micromolar inhibition of HIV-1 replication in cells attributable to an interference with the entry step of infection, by direct interaction with gp120. Inactivity of compounds toward a M475I strain suggested specific contacts with the Phe43 cavity of gp120.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / toxicity
  • Binding Sites
  • CD4 Antigens / chemistry
  • CD4 Antigens / metabolism*
  • Cell Line
  • Computer Simulation
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / metabolism*
  • HIV-1 / drug effects*
  • Humans
  • Models, Chemical
  • Phenylpropionates / chemistry*
  • Phenylpropionates / toxicity
  • Phthalimides / chemistry*
  • Phthalimides / toxicity
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • Phenylpropionates
  • Phthalimides