Identification and in silicon binding study of a novel NR2B selective NMDAR antagonist.
Identification and in silicon binding study of a novel NR2B selective NMDAR antagonist.
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DOI：
10.1016/j.bmcl.2023.129213
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发表时间：
2023-03
影响因子：
2.7
通讯作者：
Chensong Yang;Han-xun Wang;Jin Yang;Yue Zhang;Fengyun Qin;Ye-Ming He;Jiao Liu;Chao Ma;M. Cheng
中科院分区：
文献类型：
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作者：
Chensong Yang;Han-xun Wang;Jin Yang;Yue Zhang;Fengyun Qin;Ye-Ming He;Jiao Liu;Chao Ma;M. Cheng
阿尔茨海默病(AD)是威胁人类健康的一大类疾病，人们对其药物和治疗方法的研究从未停止过。作为潜在治疗靶点的NMDA受体拮抗剂的研究和开发也在进行中。本课题组根据NR2B-NMDARs靶标设计合成了22个新的四氢吡咯并[2，1-b]喹唑啉类化合物，并在体外评价了它们对NMDA诱导的细胞毒性的神经保护活性，A21表现出良好的神经保护活性。随后，通过分子对接、分子动力学(MD)模拟和结合自由能计算，进一步分析了四氢吡咯并[2，1-b]喹唑啉类化合物的构效关系和缓蚀剂结合模式。结果表明，A21能与NR2B-NMDARs的两个结合口袋相匹配。本项目的研究成果将为新型NR2B-NMDA受体拮抗剂的研究奠定一定的基础，也为该靶点的后续研究和开发提供新的思路。
Alzheimer's disease (AD) is a major group of diseases that threaten human health, and the search for drugs and treatments for it has never stopped. Research and development of NMDA receptor antagonists as potential therapeutic targets have also been ongoing. Our group designed and synthesized 22 new tetrahydropyrrolo[2,1–b]quinazolines based on NR2B-NMDARs targets and evaluated them for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, A21 exhibited excellent neuroprotective activity. Subsequently, the structure–activity relationships and inhibitor binding modes of the tetrahydropyrrolo[2,1–b]quinazolines were further analyzed by molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The results showed that A21 could match the two binding pockets of NR2B-NMDARs. The research results of this project will lay a certain foundation for the research of novel NR2B-NMDA receptor antagonists and also provide new ideas for the subsequent research and development of this target.