Expanding the chemical space of human serine racemase inhibitors.

Luca Dellafiora, Marialaura Marchetti, Francesca Spyrakis, Valentina Orlandi, Barbara Campanini, Gabriele Cruciani, Pietro Cozzini, Andrea Mozzarelli

Journal: Bioorganic & medicinal chemistry letters 2016;25(19):4297-303

PMID: 26283510

Full Text on Elsevier Science View on PubMed

Abstract

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 Ki 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 Ki values of about 1.5 mM.

Address: Department of Food Science, University of Parma, Parma, Italy.; Department of Life Sciences, University of Parma, Parma, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Department of Pharmacy, University of Parma, Parma, Italy.; Department of Pharmacy, University of Parma, Parma, Italy. Electronic address: [email protected].; Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.; Department of Food Science, University of Parma, Parma, Italy; National Institute of Biostructure and Biosystems, Rome, Italy. Electronic address: [email protected].; Department of Pharmacy, University of Parma, Parma, Italy; National Institute of Biostructure and Biosystems, Rome, Italy; Institute of Biophysics, CNR, Pisa, Italy.

DOI: 10.1016/j.bmcl.2015.07.081

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MeSH Terms: Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Hydrocarbons, Chlorinated, Malonates, Molecular Structure, Racemases and Epimerases, Structure-Activity Relationship