Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 14, Issue 5, Pages 1378-1390Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2005.09.061
Keywords
PARP-1, poly(ADP-ribose)polymerase-1; PARP-2, poly (ADP-ribose) polymerase-2 (PARP-2); NAD(+), nicotinamide adenine dinucleotide; PAR, poly(ADP-ribose); SBDD, structure based drug design; NI site, nicotinamide-ribose binding site; AD site, adenine-ribose binding site
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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. (c) 2005 Elsevier Ltd. All rights reserved.
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