In silico and pharmacological screenings identify novel serine racemase inhibitors |
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| Affiliation: | 1. Graduate School of Innovative Life Science, University of Toyama, Toyama 930-0194, Japan;2. Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan;3. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan;4. School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan;5. School of Pharmacy, Showa University, Tokyo 142-8555, Japan;6. Graduate School of Science and Technology for Research, University of Toyama, Toyama 930-8555, Japan;1. Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China;2. Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China;3. Lindsley F. Kimball Research Institute, New York Blood Center, NY 10065, USA;4. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA;5. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan;1. Diabetes Research Group, SAAD Centre for Pharmacy & Diabetes, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK;2. Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany;1. School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahi-dai, Nomi, Ishikawa 923-1292, Japan;2. Research Center for Bio-Architecture, Japan Advanced Institute of Science and Technology, 1-1 Asahi-dai, Nomi, Ishikawa 923-1292, Japan;1. Pediatric Diabetes Research Center, University of California, San Diego School of Medicine, La Jolla, California 92037 |
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| 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. |
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| Keywords: | Serine racemase inhibitors NMDA receptor In silico screening Overactivation |
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