A Fragment-Based Approach to Identifying S‑Adenosyl‑l‑methionine -Competitive Inhibitors of Catechol O‑Methyl Transferase (COMT).
datasetposted on 26.06.2014 by 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
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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’s 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 = 0.33–0.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.