Activities, crystal structures, and molecular dynamics of dihydro-1H-isoindole derivatives, inhibitors of HIV-1 integrase

ACS Chem Biol. 2013 Jan 18;8(1):209-17. doi: 10.1021/cb300471n. Epub 2012 Dec 24.


On the basis of a series of lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed a new molecule, XZ-259, with biochemical and antiviral activities comparable to raltegravir. We determined the crystal structures of XZ-259 and four other derivatives in complex with the prototype foamy virus intasome. The compounds bind at the integrase-Mg(2+)-DNA interface of the integrase active site. In biochemical and antiviral assays, XZ-259 inhibits raltegravir-resistant HIV-1 integrases harboring the Y143R mutation. Molecular modeling is also presented suggesting that XZ-259 can bind in the HIV-1 intasome with its dimethyl sulfonamide group adopting two opposite orientations. Molecular dynamics analyses of the HIV-1 intasome highlight the importance of the viral DNA in drug potency.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Crystallography, X-Ray
  • HIV Integrase Inhibitors* / chemistry
  • HIV Integrase Inhibitors* / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Isoindoles / chemistry*
  • Isoindoles / pharmacology
  • Molecular Dynamics Simulation*
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology


  • Antiviral Agents
  • HIV Integrase Inhibitors
  • Isoindoles
  • Sulfonamides
  • XZ-259

Associated data

  • PDB/4BDY
  • PDB/4BDZ
  • PDB/4BE0
  • PDB/4BE1
  • PDB/4BE2