title: In silico and pharmacological screenings identify novel serine racemase inhibitors.
abstract: D-Serine is a coagonist of the N-methyl-D-aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by serine racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50 value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.
authors: Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan; Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Hisashi
authors: H
authors: Mori
authors: Graduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan.
authors: Ryogo
authors: R
authors: Wada
authors: Graduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan.
authors: Jie
authors: J
authors: Li
authors: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Tetsuya
authors: T
authors: Ishimoto
authors: Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan; Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Mineyuki
authors: M
authors: Mizuguchi
authors: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
authors: Takayuki
authors: T
authors: Obita
authors: School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan; School of Pharmacy, Showa University, Tokyo 142-8555, Japan.
authors: Hiroaki
authors: H
authors: Gouda
authors: School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan.
authors: Shuichi
authors: S
authors: Hirono
authors: Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan; Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan.
authors: Naoki
authors: N
authors: Toyooka
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099300:Serine Racemase
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D019998:Racemases and Epimerases; D000099300:Serine Racemase
keywords: In silico screening; NMDA receptor; Overactivation; Serine racemase inhibitors; d-Serine