Takahara Satoyuki, Nakagawa Kiyomi, Uchiyama Tsugumi, Yoshida Tomoyuki, Matsumoto Kazunori, Kawasumi Yasuo, Mizuguchi Mineyuki, Obita Takayuki, Watanabe Yurie, Hayakawa Daichi, Gouda Hiroaki, Mori Hisashi, Toyooka Naoki
Graduate School of Innovative Life Science, University of Toyama, Japan.
Graduate School of Science and Engineering, University of Toyama, Japan.
Bioorg Med Chem Lett. 2018 Feb 1;28(3):441-445. doi: 10.1016/j.bmcl.2017.12.021. Epub 2017 Dec 13.
Most of the endogenous free d-serine (about 90%) in the brain is produced by serine racemase (SR). d-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR. Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR.
大脑中大部分内源性游离 D-丝氨酸（约 90%）由丝氨酸消旋酶（SR）产生。大脑中的 D-丝氨酸作为 N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的内源性共激动剂，参与神经退行性疾病和癫痫状态。因此，SR 抑制剂有望成为治疗这些疾病的新型候选药物。在本研究中，我们解析了野生型 SR 的晶体结构，并尝试利用该结构信息通过计算机筛选来鉴定一种新的 SR 抑制剂。结果，通过使用野生型 SR 的体外评估，我们鉴定出了两种有活性的化合物。基于活性更强的命中化合物 1 的结构，我们合成了 15 种衍生物，并评估了它们对野生型 SR 的抑制活性。其中，化合物 9C 对野生型 SR 表现出相对较高的抑制效力。化合物 9C 是一种比化合物 24 更有效的抑制剂，化合物 24 是我们小组根据突变型 SR 的结构信息合成的。
