Expanding the chemical space of human serine racemase inhibitors. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Dellafiora, Luca; Marchetti, Marialaura; Spyrakis, Francesca; Orlandi, Valentina; Campanini, Barbara; Cruciani, Gabriele; Cozzini, Pietro; Mozzarelli, Andrea
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4297
• Page End: 4303
• Publication Date: 2015-10-01
• Subjects: Human serine racemase -- PLP-dependent enzymes -- FLAP -- NMDAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.07.081
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Serine racemase, the enzyme responsible ford -serine synthesis in the central nervous system, has been identified as a potential therapeutic target to treat N -methyl-d -aspartate receptors-related pathologies. The search for specific inhibitors of the enzyme has revealed that serine racemase is a difficult target, with the best inhibitor currently identified, 2, 2-dichloromalonate, showing a K i of 19 μM. In order to expand the chemical space of hit compounds, we have performed an in silico structure-based screening campaign on a filtered ZINC library applying the FLAP software. The identified hits were docked with GOLD and re-scored with HINT, and the most promising molecules experimentally evaluated on recombinant human serine racemase. Two inhibitors, with chemical structures totally unrelated to inhibitors described so far showed K i values of about 1.5 mM.