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Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activityстатья
- Авторы: 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.
- Журнал: RSC Medicinal Chemistry
- Том: 13
- Номер: 7
- Год издания: 2022
- Издательство: Royal Society of Chemistry
- Местоположение издательства: United Kingdom
- Первая страница: 822
- Последняя страница: 830
- DOI: 10.1039/d2md00001f
- Аннотация: NMDA (N-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 (IC50 = 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.
- Добавил в систему: Палюлин Владимир Александрович