Тип публикации: статья из журнала
Год издания: 2017
Идентификатор DOI: 10.1039/c7ra00496f
Ключевые слова: Binding energy, Dihedral angle, Molecular dynamics, Neurodegenerative diseases, Positron emission tomography, Van der Waals forces, Alzheimer's disease, Crystalline structure, Metadynamics simulations, Molecular docking, Neurological disorders, Nicotinic acetylcholine receptors, Positron emission tomography (PET), Van Der Waals interactions, Bins
Аннотация: The ?7 nicotinic acetylcholine receptor (?7-nAChR) is assumed to be implicated in a variety of neurological disorders, such as schizophrenia and Alzheimer's disease (AD). The progress of these disorders can be studied through imaging ?7-nAChR with positron emission tomography (PET). [18F]ASEM is a novel and potent ?7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [18F]ASEM and ?7-nAChR is still unclear. In this paper, the binding profile of [18F]ASEM to a chimera structure of ?7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [18F]ASEM binds at the same site as the crystallized agonist epibatidine but with a different binding mode. The dibenzo[b,d]thiophene ring has a different orientation compared to the pyridine ring of epibatidine and has van der Waals interactions with residues from loop C on one side and ?-? stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [18F]ASEM. Six binding modes in terms of the side chain dihedral angles ?1 and ?2 of Trp53 were discovered by metadynamics simulation. In the most stable binding mode, Trp53 adopts a different conformation from that in the crystalline structure and has a rather favorable ?-? stacking interaction with [18F]ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands. © The Royal Society of Chemistry.
Журнал: RSC Advances
Выпуск журнала: Vol. 7, Is. 32
Номера страниц: 19787-19793
ISSN журнала: 20462069
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