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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Authors: | Ishida Junya Yamamoto Hirofumi Kido Yoshiyuki Kamijo Kazunori Murano Kenji Miyake Hiroshi Ohkubo Mitsuru Kinoshita Takayoshi Warizaya Masaichi Iwashita Akinori Mihara Kayoko Matsuoka Nobuya Hattori Kouji |
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Institution: | Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Tsukuba, Ibaraki, Japan. |
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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. |
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