Karlov Dmitry S, Temnyakova Nadezhda S, Vasilenko Dmitry A, Barygin Oleg I, Dron Mikhail Y, Zhigulin Arseniy S, Averina Elena B, Grishin Yuri K, Grigoriev Vladimir V, Gabrel'yan Alexey V, Aniol Viktor A, Gulyaeva Natalia V, Osipenko Sergey V, Kostyukevich Yury I, Palyulin Vladimir A, Popov Petr A, Fedorov Maxim V
Skolkovo Institute of Science and Technology, Skolkovo Innovation Center 143026 Moscow Russian Federation
Department of Chemistry, Lomonosov Moscow State University 119991 Moscow Russian Federation.
RSC Med Chem. 2022 Jun 22;13(7):822-830. doi: 10.1039/d2md00001f. eCollection 2022 Jul 20.
NMDA (-methyl-d-aspartate) receptor antagonists are promising tools for the treatment of a wide variety of central nervous system impairments including major depressive disorder. We present here the activity optimization process of a biphenyl-based NMDA negative allosteric modulator (NAM) guided by free energy calculations, which led to a 100 times activity improvement (IC = 50 nM) compared to a hit compound identified in virtual screening. Preliminary calculation results suggest a low affinity for the human ether-a-go-go-related gene ion channel (hERG), a high affinity for which was earlier one of the main obstacles for the development of first-generation NMDA-receptor negative allosteric modulators. The docking study and the molecular dynamics calculations suggest a completely different binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101.
N-甲基-D-天冬氨酸（NMDA）受体拮抗剂是治疗包括重度抑郁症在内的多种中枢神经系统损伤的有前景的工具。我们在此展示了一个基于联苯的NMDA负性变构调节剂（NAM）的活性优化过程，该过程由自由能计算指导，与虚拟筛选中鉴定出的一个先导化合物相比，活性提高了100倍（IC = 50 nM）。初步计算结果表明其对人醚-去极化相关基因离子通道（hERG）的亲和力较低，而对hERG的高亲和力是第一代NMDA受体负性变构调节剂开发的主要障碍之一。对接研究和分子动力学计算表明，与另一种基于联芳基的NMDA NAM EVT-101相比，其结合模式完全不同（类ifenprodil）。
