Glutamate receptor antagonist perampanel: Quantum chemistry and molecular docking studies

Guseynov, A.D.; Pisarev, S.A.; Shulga, D.A.; Palyulin, V.A.; Fedorov, M.V.; Karlov, D.S.

Авторы: Guseynov A.D., Pisarev S.A., Shulga D.A., Palyulin V.A., Fedorov M.V., Karlov D.S.
Сборник: 15th German Conference on Cheminformatics, Mainz, Germany, November 3-5, 2019
Тезисы
Год издания: 2019
Место издания: Mainz, Germany
Первая страница: 100
Последняя страница: 100
Аннотация: Ionotropic glutamate receptors are ligand-gated ion channels responsible for fast synaptic transmission throughout the vertebrate nervous system. Their inhibition is considered to be perspective for the treatment of a wide range of neurological impairments and is currently used against epilepsy. Perampanel is the first drug approved by FDA and acting through noncompetitive inhibition of the AMPA subtype ionotropic glutamate receptors. Minor structural modifications of this drug lead to a sharp activity decrease, an effect called "activity cliff". Recent crystallographic studies allowed the application of structure-based approaches to the analysis of perampanel binding to the target protein. In our work, we study the reasons behind the reported activity cliffs. First, a DFT level conformational space investigation followed by the intramolecular interactions analysis was conducted for perampanel and a number of its close structural analogs. Then, a robust and fully flexible molecular docking was carried out for the same set of molecules. Its results suggested an additional binding mode for perampanel, which is in agreement with mutagenesis data and is generally consistent with experimental 2Fo-Fc electron density. The suggested binding mode provides a reasonable explanation for the reported activity cliffs.
Добавил в систему: Радченко Евгений Валерьевич

	ИСТИНА	Войти в систему Регистрация
	ИСТИНА ИНХС РАН
	Главная Поиск Статистика О проекте Помощь

ИСТИНА

ИСТИНА ИНХС РАН

Glutamate receptor antagonist perampanel: Quantum chemistry and molecular docking studiesтезисы доклада

Прикрепленные файлы