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Nicotinic acetylcholine receptors and their interactions with allosteric ligands

Newcombe, Joseph; (2018) Nicotinic acetylcholine receptors and their interactions with allosteric ligands. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand gated ion channels (pLGICs) expressed widely throughout the body, including in the peripheral nervous system, central nervous system and at the neuromuscular junction. nAChRs are of therapeutic interest due to their involvement in several pathophysiological conditions. The most widely expressed nAChR subtypes, α7 and α4β2 have attracted a lot of attention and many allosteric ligands have been pharmacologically and chemically characterised for these receptors. However, much remains to be understood about where and how these ligands bind to the receptors and modulate their function. This thesis has focussed on a set of transmembrane binding allosteric modulators for the α7 nAChR and sought to aid understanding of their interactions with their target receptor by building models of nAChRs in physiologically relevant states. A transmembrane error in the only example of a pLGIC structure determined in a native lipid membrane environment, the T. marmorata nAChR, has been corrected through modelling and refinement into previously determined electron cryo-microscopy density maps, in putative closed and open conformations. The refined models offer important reference structures for anyone working in the pLGIC field and here have been used as templates to model the α7 nAChR. A consensus docking protocol has been developed and was utilised in conjunction with the α7 models to predict binding modes for a set of allosteric modulators and provide insight into how they may elicit distinct pharmacology. Based on binding modes of allosteric modulators predicted by the consensus docking protocol, pharmacophores were generated for use in ligand-based virtual screening and allosteric modulators have been uncovered for α7 and α4β2 nAChRs from the existing pharmacopeia. Further to this, novel reactive chemical probes have been developed and synthesised to study the covalent incorporation of allosteric modulators into nAChRs.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Nicotinic acetylcholine receptors and their interactions with allosteric ligands
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords: nAChR, Allosteric modulators, Docking, Protein modelling, Cryo EM
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10062774
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