In silico and pharmacological screenings identify novel serine racemase inhibitors

Hisashi Mori; Ryogo Wada; Jie Li; Tetsuya Ishimoto; Mineyuki Mizuguchi; Takayuki Obita; Hiroaki Gouda; Shuichi Hirono; Naoki Toyooka

doi:10.1016/j.bmcl.2014.07.003

In silico and pharmacological screenings identify novel serine racemase inhibitors

Hisashi Mori^*, Ryogo Wada, Jie Li, Tetsuya Ishimoto, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Pages (from-to)	3732-3735
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2014.07.003
State	Published - 2014/08/15

Keywords

In silico screening
NMDA receptor
Overactivation
Serine racemase inhibitors
d-Serine

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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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.",

keywords = "In silico screening, NMDA receptor, Overactivation, Serine racemase inhibitors, d-Serine",

author = "Hisashi Mori and Ryogo Wada and Jie Li and Tetsuya Ishimoto and Mineyuki Mizuguchi and Takayuki Obita and Hiroaki Gouda and Shuichi Hirono and Naoki Toyooka",

note = "Funding Information: We thank Riken NBRC and Prof. Yoshimura for providing the hSR cDNA clone and the Dsd1SC expression vector, respectively. This work was supported by Grants from Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant Nos. 221S0003 and 25293059 to H.M.) and the research fund of University of Toyama. ",

year = "2014",

month = aug,

day = "15",

doi = "10.1016/j.bmcl.2014.07.003",

language = "英語",

volume = "24",

pages = "3732--3735",

journal = "Bioorganic and Medicinal Chemistry Letters",

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TY - JOUR

T1 - In silico and pharmacological screenings identify novel serine racemase inhibitors

AU - Mori, Hisashi

AU - Wada, Ryogo

AU - Li, Jie

AU - Ishimoto, Tetsuya

AU - Mizuguchi, Mineyuki

AU - Obita, Takayuki

AU - Gouda, Hiroaki

AU - Hirono, Shuichi

AU - Toyooka, Naoki

N1 - Funding Information: We thank Riken NBRC and Prof. Yoshimura for providing the hSR cDNA clone and the Dsd1SC expression vector, respectively. This work was supported by Grants from Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant Nos. 221S0003 and 25293059 to H.M.) and the research fund of University of Toyama.

PY - 2014/8/15

Y1 - 2014/8/15

N2 - 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.

AB - 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.

KW - In silico screening

KW - NMDA receptor

KW - Overactivation

KW - Serine racemase inhibitors

KW - d-Serine

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DO - 10.1016/j.bmcl.2014.07.003

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AN - SCOPUS:84905902068

SN - 0960-894X

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 16

ER -

In silico and pharmacological screenings identify novel serine racemase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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