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  • Kuang, GuanglinKTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden. (author)

Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • 2017
  • Royal Society of Chemistry,2017
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:kth-207402
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-207402URI
  • https://doi.org/10.1039/c7ra00496fDOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:135687740URI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-322119URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20170601
  • The α7 nicotinic acetylcholine receptor (α7-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 α7-nAChR with positron emission tomography (PET). [18F]ASEM is a novel and potent α7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [18F]ASEM and α7-nAChR is still unclear. In this paper, the binding profile of [18F]ASEM to a chimera structure of α7-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 π-π 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 χ1 and χ2 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 π-π stacking interaction with [18F]ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.

Subject headings and genre

  • NATURVETENSKAP Kemi hsv//swe
  • NATURAL SCIENCES Chemical Sciences hsv//eng
  • 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

Added entries (persons, corporate bodies, meetings, titles ...)

  • Zhou, Yang,1986-KTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.(Swepub:kth)u1qoay2o (author)
  • Zou, RongfengKTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.(Swepub:kth)u1808q2l (author)
  • Halldin, C.Karolinska Institutet,Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden. (author)
  • Nordberg, A.Karolinska Institutet,Karolinska Univ Hosp, Ctr Alzheimer Res Translat Alzheimer Neurobiol, Dept Neurobiol Care Sci & Soc, S-14186 Huddinge, Sweden. (author)
  • Långström, BengtUppsala universitet,Organisk kemi(Swepub:uu)benglang (author)
  • Ågren, HansKTH,Teoretisk kemi och biologi,Siberian Federal University, Russian Federation,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.(Swepub:kth)u1l2s96v (author)
  • Tu, YaoquanKTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.(Swepub:kth)u1kuh2ie (author)
  • KTHTeoretisk kemi och biologi (creator_code:org_t)

Related titles

  • In:RSC Advances: Royal Society of Chemistry7:32, s. 19787-197932046-2069

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