title: Cyclopropane derivatives as potential human serine racemase inhibitors: unveiling novel insights into a difficult target.
abstract: d-Serine is the co-agonist of NMDA receptors and binds to the so-called glycine site. d-Serine is synthesized by human serine racemase (SR). Over activation of NMDA receptors is involved in many neurodegenerative diseases and, therefore, the inhibition of SR might represent a novel strategy for the treatment of these pathologies. SR is a very difficult target, with only few compounds so far identified exhibiting weak inhibitory activity. This study was aimed at the identification of novel SR inhibitor by mimicking malonic acid, the best-known SR inhibitor, with a cyclopropane scaffold. We developed, synthesized, and tested a series of cyclopropane dicarboxylic acid derivatives, complementing the synthetic effort with molecular docking. We identified few compounds that bind SR in high micromolar range with a lack of significant correlation between experimental and predicted binding affinities. The thorough analysis of the results can be exploited for the development of more potent SR inhibitors.
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .
authors.forename: Claudia
authors.initials: C
authors.lastname: Beato
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .
authors.forename: Chiara
authors.initials: C
authors.lastname: Pecchini
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .
authors.forename: Chiara
authors.initials: C
authors.lastname: Cocconcelli
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .
authors.forename: Barbara
authors.initials: B
authors.lastname: Campanini
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .
authors.forename: Marialaura
authors.initials: M
authors.lastname: Marchetti
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .|b Istituto Nazionale Biostrutture e Biosistemi -- Consorzio Interuniversitario , Roma , Italy , and.|c Istituto di Biofisica, CNR , Pisa , Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
authors.affiliation: a Dipartimento di Farmacia , Università degli studi di Parma , Parma , Italy .
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
mesh_terms: D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099300:Serine Racemase
chemical_list: D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D019998:Racemases and Epimerases; D000099300:Serine Racemase; C030797:cyclopropane
keywords: Conformational ensemble; cyclopropane; inhibition; molecular docking; serine racemase