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 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.
Department of Food Science, University of Parma, Parma, Italy.
Luca
L
Dellafiora
Department of Life Sciences, University of Parma, Parma, Italy.
Marialaura
M
Marchetti
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Francesca
F
Spyrakis
Department of Pharmacy, University of Parma, Parma, Italy.
Valentina
V
Orlandi
Department of Pharmacy, University of Parma, Parma, Italy. Electronic address: barbara.campanini@unipr.it.
Barbara
B
Campanini
Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
Gabriele
G
Cruciani
Department of Food Science, University of Parma, Parma, Italy; National Institute of Biostructure and Biosystems, Rome, Italy. Electronic address: pietro.cozzini@unipr.it.
Pietro
P
Cozzini
Department of Pharmacy, University of Parma, Parma, Italy; National Institute of Biostructure and Biosystems, Rome, Italy; Institute of Biophysics, CNR, Pisa, Italy.
Andrea
A
Mozzarelli
D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008314:Malonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099300:Serine Racemase
D004791:Enzyme Inhibitors; D006843:Hydrocarbons, Chlorinated; D008314:Malonates; D019998:Racemases and Epimerases; D000099300:Serine Racemase
FLAP; Human serine racemase; NMDAR; PLP-dependent enzymes