Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling.
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Ishida J, Yamamoto H, Kido Y, Kamijo K, Murano K, Miyake H, Ohkubo M, Kinoshita T, Warizaya M, Iwashita A, Mihara K, Matsuoka N, Hattori K
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. Epub 2005 Nov 8.
- PubMed ID
- 16288880 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 2-(4-Chlorophenyl)-5-Quinoxalinecarboxamide Poly [ADP-ribose] polymerase 1 IC 50 (nM) 33 8 23 Details 2-{3-[4-(4-Fluorophenyl)-3,6-Dihydro-1(2h)-Pyridinyl]Propyl}-8-Methyl-4(3h)-Quinazolinone Poly [ADP-ribose] polymerase 1 IC 50 (nM) 16 8 23 Details 5-FLUORO-1-[4-(4-PHENYL-3,6-DIHYDROPYRIDIN-1(2H)-YL)BUTYL]QUINAZOLINE-2,4(1H,3H)-DIONE Poly [ADP-ribose] polymerase 1 IC 50 (nM) 60 8 23 Details