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Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the alpha 7 nicotinic acetylcholine receptor
AlbaNova Univ Ctr, Sch Biotechnol, Royal Inst Technol KTH, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
AlbaNova Univ Ctr, Sch Biotechnol, Royal Inst Technol KTH, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden..
Karolinska Univ Hosp, Ctr Alzheimer Res Translat Alzheimer Neurobiol, Dept Neurobiol Care Sci & Soc, S-14186 Stockholm, Sweden..
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2016 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 18, no 40, 28003-28009 p.Article in journal (Refereed) Published
Abstract [en]

Potentiation of the function of the alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is believed to provide a possible way for the treatment of cholinergic system dysfunctions such as Alzheimer's disease and schizophrenia. Positive allosteric modulators (PAMs) are able to augment the peak current response of the endogenous agonist of alpha 7-nAChR by binding to some allosteric sites. In this study, the binding profile of a potent type I PAM, NS-1738, with a chimera structure (termed alpha 7-AChBP) constructed from the extracellular domain of alpha 7-nAChR and an acetylcholine binding protein was investigated with molecular docking, molecular dynamics simulation, and free energy calculation methods. We found that NS-1738 could bind to three allosteric sites of alpha 7-AChBP, namely, the top pocket, the vestibule pocket and the agonist sub-pocket. NS-1738 has moderate binding affinities (-6.76 to -9.15 kcal mol(-1)) at each allosteric site. The urea group is critical for binding and can form hydrogen-bond interactions with the protein. The bulky trifluoromethyl group also has a great impact on the binding modes and binding affinities. We believe that our study provides valuable insight into the binding profiles of type I PAMs with alpha 7-nAChR and is helpful for the development of novel PAMs.

Place, publisher, year, edition, pages
2016. Vol. 18, no 40, 28003-28009 p.
National Category
Organic Chemistry Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-307524DOI: 10.1039/c6cp02278bISI: 000385180600033PubMedID: 27711412OAI: oai:DiVA.org:uu-307524DiVA: diva2:1047472
Funder
Swedish Foundation for Strategic Research , RB13-0192Swedish National Infrastructure for Computing (SNIC), m.2015-1-396Stockholm County Council, K1764-2013
Available from: 2016-11-17 Created: 2016-11-17 Last updated: 2016-11-17Bibliographically approved

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Långström, Bengt
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