Volume 6 Supplement 1

9th German Conference on Chemoinformatics

Open Access

Dualsteric modulators of the M2 muscarinic acetylcholine receptor

  • Marcel Bermudez1 and
  • Gerhard Wolber1
Journal of Cheminformatics20146(Suppl 1):P40

https://doi.org/10.1186/1758-2946-6-S1-P40

Published: 11 March 2014

G-protein coupled receptors (GPCRs) trigger multiple signal-switching mechanisms like binding of ß-arrestin proteins, activation of kinases and G-protein activation [1]. The poor understanding of the conformational changes resulting in these activations is a major challenge for the design of specific GPCR modulating drugs. For the muscarinic M2 receptor, allosteric, orthosteric and dualsteric binding small molecules are available, which helps to elucidate multiple signaling roles [24]. The recently published crystal structure of the M2 muscarinic acetylcholine receptor (PDB: 3UON [5]) and mutational studies offer the possibility to rationalize and understand the binding of ligands to muscarinic acetylcholine receptors.

We present the results of extensive molecular dynamics simulations in combination with docking and 3D-pharmacophore analyses of known ligands (atropine and scopolamine) and their related dualsteric hybrid structures (JSW253, JSW257, JSW254 and JSW256). Insights into the flexibility of the allosteric binding pocket confirm earlier hypotheses: A comparison of dualsteric hybrid structures proves the crucial role of the tropane ring system for the arrangement of the allosteric part of the ligands. Whereas the extracellular loop 2 is engaged in the binding of the scopolamine-based hybrid structures, it plays a minor role for the binding of atropine-based dualsteric ligands. Orthosteric ligand binding was similar for all ligands and characterized by an essential electrostatic interaction and an aromatic cage.

Authors’ Affiliations

(1)
Computer-Aided Drug Design, Institute of Pharmacy, Freie Universität Berlin

References

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Copyright

© Bermudez and Wolber; licensee Chemistry Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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