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Positive allosteric modulators of AMPA receptors: from molecular dynamics to preclinical studiesтезисы доклада
- Авторы: Palyulin V.A., Lavrov M.I., Karlov D.S., Grigoriev V.V., Bachurin S.O., Zefirov N.S.
- Сборник: 21st European Symposium on Quantitative Structure-Activity Relationship: Where Molecular Simulations Meet Drug Discovery, Verona, Italy, September 4-8, 2016
- Тезисы
- Год издания: 2016
- Место издания: Verona, Italy
- Первая страница: P196
- Аннотация: Glutamatergic system plays an important role in the functioning of mammals CNS. Positive allosteric modulators (PAMs) of AMPA receptors (one of types of ionotropic glutamate receptors) have a significant influence on learning and memory consolidation. It is also shown in experiments that the intensive ion currents caused by such modulators and further postsynaptic membrane depolarization launch the mechanism of gene expression responsible for the synthesis of NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor). Thus the drugs having this mechanism of action could be efficient for the treatment of neurodegenerative diseases. AMPA receptors are ligand-gated ionotropic receptors consisting of four subunits forming the ion channel, ligand-binding domains, and amino-terminal domains. The molecular modeling and molecular dynamics simulations for a series of AMPA receptor positive allosteric modulators (PAMs) bound on the interface between two glutamate-binding domains have demonstrated a reasonable correlation of MM-GBSA binding energy with experimental pEC50 values. The combination of the considered techniques with QSAR studies of ligand-receptor interactions allowed us to design new scaffolds for PAMs and have lead to the development of a picomolar positive AMPA receptor modulator with a record high potency shown in electrophysiological experiments (patch-clamp). In animal models this compound improves memory and cognition in low doses. In preclinical studies it demonstrated extremely low toxicity (LD50 > 5 g/kg) and the absence of other side effects.
- Добавил в систему: Радченко Евгений Валерьевич