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
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