A Fragment-Based Approach to Identifying S‑Adenosyl‑l‑methionine -Competitive Inhibitors of Catechol O‑Methyl Transferase (COMT).
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posted on 2014-06-26, 00:00 authored 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. HixonCatechol 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.
