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Characterization of the binding mode of the PET tracer [F-18] ASEM to a chimera structure of the alpha 7 nicotinic acetylcholine receptor
Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden..
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2017 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 32, 19787-19793 p.Article in journal (Refereed) Published
Abstract [en]

The alpha 7 nicotinic acetylcholine receptor (alpha 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 alpha 7-nAChR with positron emission tomography (PET). [F-18]ASEM is a novel and potent alpha 7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [F-18] ASEM and alpha 7-nAChR is still unclear. In this paper, the binding profile of [F-18] ASEM to a chimera structure of alpha 7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [F-18] 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 p-p stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [F-18] ASEM. Six binding modes in terms of the side chain dihedral angles chi(1) and chi(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 pi-pi stacking interaction with [F-18] ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017. Vol. 7, no 32, 19787-19793 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-322119DOI: 10.1039/c7ra00496fISI: 000399242100041OAI: oai:DiVA.org:uu-322119DiVA: diva2:1095968
Funder
Swedish Foundation for Strategic Research , RB13-0192Stockholm County Council, K1764-2013Swedish National Infrastructure for Computing (SNIC), m.2015-1-396
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-19Bibliographically approved

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