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

Article Details

Citation

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
DrugTargetPropertyMeasurementpHTemperature (°C)
2-(4-Chlorophenyl)-5-QuinoxalinecarboxamidePoly [ADP-ribose] polymerase 1IC 50 (nM)33823Details
2-{3-[4-(4-Fluorophenyl)-3,6-Dihydro-1(2h)-Pyridinyl]Propyl}-8-Methyl-4(3h)-QuinazolinonePoly [ADP-ribose] polymerase 1IC 50 (nM)16823Details
5-FLUORO-1-[4-(4-PHENYL-3,6-DIHYDROPYRIDIN-1(2H)-YL)BUTYL]QUINAZOLINE-2,4(1H,3H)-DIONEPoly [ADP-ribose] polymerase 1IC 50 (nM)60823Details