A platform for designing HIV integrase inhibitors. Part 2: a two-metal binding model as a potential mechanism of HIV integrase inhibitors

Bioorg Med Chem. 2006 Dec 15;14(24):8420-9. doi: 10.1016/j.bmc.2006.08.043. Epub 2006 Sep 26.

Abstract

We propose a two-metal binding model as a potential mechanism of chelating inhibitors against HIV integrase (HIV IN) represented by 2-hydroxy-3-heteroaryl acrylic acids (HHAAs). Potential inhibitors would bind to two metal ions in the active site of HIV IN to prevent human DNA from undergoing the integration reaction. Correlation of the results of metal (Mg(2+) and Mn(2+)) titration studies with HIV IN inhibition for a series of active and inactive compounds provides support for the model. Results suggest Mg(2+) is an essential cofactor for chelating inhibitors.

MeSH terms

  • Acrylates / chemical synthesis
  • Acrylates / chemistry*
  • Acrylates / pharmacology
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Binding Sites
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Drug Design
  • HIV Integrase / chemistry*
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects*
  • Humans
  • Magnesium / metabolism*
  • Manganese / metabolism*
  • Models, Biological
  • Models, Molecular*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Acrylates
  • Anti-HIV Agents
  • Chelating Agents
  • HIV Integrase Inhibitors
  • Manganese
  • HIV Integrase
  • Magnesium