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Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling
- Source :
-
Bioorganic & Medicinal Chemistry . Mar2006, Vol. 14 Issue 5, p1378-1390. 13p. - Publication Year :
- 2006
-
Abstract
- 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. [Copyright &y& Elsevier]
- Subjects :
- *RNA polymerases
*X-rays
*DRUG design
*THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 14
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19465146
- Full Text :
- https://doi.org/10.1016/j.bmc.2005.09.061