In Silico and In Vitro Screening of Serine Racemase Agonist and In Vivo Efficacy on Alzheimer's Disease Drosophila melanogaster

Chih-Hao Lu; Hao-Teng Chang; Lee-Fen Hsu; Ming-Hsueh Lee; Jack Cheng; Dong Chuan Wu; Wei-Yong Lin

doi:10.3390/ph16020280

In Silico and In Vitro Screening of Serine Racemase Agonist and In Vivo Efficacy on Alzheimer's Disease Drosophila melanogaster

Pharmaceuticals (Basel). 2023 Feb 13;16(2):280. doi: 10.3390/ph16020280.

Authors

Chih-Hao Lu^{1

2}, Hao-Teng Chang³, Lee-Fen Hsu^{4

5

6}, Ming-Hsueh Lee⁶, Jack Cheng^{7

8}, Dong Chuan Wu^{3

9}, Wei-Yong Lin^{7

8

10}

Affiliations

¹ Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan.
² Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan.
³ Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan.
⁴ Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi City 613, Chiayi County, Taiwan.
⁵ Chronic Disease and Health Promotion Research Center, Chang Gung University of Science and Technology, Puzi City 613, Chiayi County, Taiwan.
⁶ Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Puzi City 613, Chiayi County, Taiwan.
⁷ Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan.
⁸ Department of Medical Research, China Medical University Hospital, Taichung 40402, Taiwan.
⁹ Translational Medicine Research Center, China Medical University Hospital, Taichung 40402, Taiwan.
¹⁰ Brain Diseases Research Center, China Medical University, Taichung 40402, Taiwan.

Abstract

The NMDA receptor hypofunction has been implicated in schizophrenia, memory impairment, and Alzheimer's disease. Modulating the abundance of D-serine, a co-agonist of the NMDA receptor, is a strategy to treat symptoms of the NMDA receptor hypofunction. In contrast to D-amino acid oxidase (DAAO) inhibitors, which aim at decreasing the loss of D-serine, this study tried to identify serine racemase (SRR) agonists, which boost the conversion of L-serine to D-serine. We used holo and apo structures of human SRR for the molecular docking against the National Cancer Institute (NCI) and ZINC compound databases and validated their efficacy by in vitro SRR activity assay. We identified NSC294149 (2-amino-3-(3-nitroimidazo[1,2-a]pyridin-2-yl)sulfanylpropanoic acid) as a potential SRR agonist and confirmed its amelioration of the hazard ratio of survival of the AD model of fruit fly (Drosophila melanogaster). These results suggest that the SRR agonist could be a drug design target against the NMDA receptor hypofunction symptoms.

Keywords: D-serine; NMDA receptor hypofunction; drug development; serine racemase.

Abstract

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