Expanding the chemical space of human serine racemase inhibitors

Serine racemase, the enzyme responsible for D-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 mu M. 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.