Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling

Bioorg Med Chem. 2006 Mar 1;14(5):1378-90. doi: 10.1016/j.bmc.2005.09.061. Epub 2005 Nov 8.


We disclose herein our efforts aimed at discovery of selective PARP-1 and PARP-2 inhibitors. We have recently discovered several novel classes of quinazolinones, quinazolidinones, and quinoxalines as potent PARP-1 inhibitors, which may represent attractive therapeutic candidates. In PARP enzyme assays using recombinant PARP-1 and PARP-2, the quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2, and the quinazolidinone derivatives did not have selectivity for PARP-1/2. Structure-based drug design analysis via a combination of X-ray structural study utilizing the complexes of inhibitors and human PARP-1 catalytic domain, and homology modeling using murine PARP-2 suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Models, Chemical
  • Models, Molecular
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacology
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / pharmacology
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinazolines
  • Quinoxalines
  • PARP1 protein, human
  • PARP2 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases