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  3. Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the ?7 nicotinic acetylcholine receptor

Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the ?7 nicotinic acetylcholine receptor

Описание

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 radiПоказать полностьюoligand 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.

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Издание

Журнал: RSC Advances

Выпуск журнала: Vol. 7, Is. 32

Номера страниц: 19787-19793

Персоны

  • Kuang Guanglin (Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden)
  • Zhou Yang (Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden)
  • Zou Rongfeng (Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden)
  • Halldin Christer (Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden)
  • Nordberg Agneta (Karolinska Univ Hosp, Ctr Alzheimer Res Translat Alzheimer Neurobiol, Dept Neurobiol Care Sci & Soc, S-14186 Huddinge, Sweden)
  • Langstrom Bengt (Uppsala Univ, Dept Chem, S-75123 Uppsala, Sweden)
  • Agren Hans (Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden; Siberian Fed Univ, Inst Nanotechnol Spect & Quantum Chem, Svobodny Pr 79, Krasnoyarsk 660041, Russia)
  • Tu Yaoquan (Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden)

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