A Fragment-Based Approach to Identifying S-Adenosyl-l-methionine -Competitive Inhibitors of Catechol O-Methyl Transferase (COMT).
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- 作者：Marion Lanier ; Geza Ambrus ; Derek C. Cole ; Richard Davenport ; Jonathan Ellery ; Richard Fosbeary ; Andy J. Jennings ; Akito Kadotani ; Yusuke Kamada ; Ruhi Kamran ; Shin-Ichi Matsumoto ; Atsushi Mizukami ; Shoichi Okubo ; Kengo Okada ; Kumar Saikatendu ; Louise Walsh ; Haihong Wu ; Mark S. Hixon
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：June 26, 2014
- 年：2014
- 卷：57
- 期：12
- 页码：5459-5463
- 全文大小：295K
- ISSN：1520-4804
文摘
Catechol O-methyl transferase belongs to the diverse family of S-adenosyl-l-methionine transferases. It is a target involved in the treatment of Parkinson鈥檚 disease. Here we present a fragment-based screening approach to discover noncatechol derived COMT inhibitors which bind at the SAM binding pocket. We describe the identification and characterization of a series of highly ligand efficient SAM competitive bisaryl fragments (LE = 0.33鈥?.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.