A Fragment-Based Approach to Identifying <i>S</i>‑Adenosyl‑l‑methionine -Competitive Inhibitors of Catechol <i>O</i>‑Methyl Transferase (COMT).

Catechol <i>O</i>-methyl transferase belongs to the diverse family of <i>S</i>-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.