Caseley, EA, Muench, SP, Baldwin, SA et al. (3 more authors) (2015) Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human. Bioorganic and Medicinal Chemistry Letters, 25 (16). 3164 - 3167. ISSN 0960-894X
Abstract
The P2X7 receptor is a calcium permeable cationic channel activated by extracellular ATP, playing a role in chronic pain, osteoporosis and arthritis. A number of potential lead compounds are inactive against the rat isoform, despite good activity against the human homologue, making animal model studies problematic. Here we have produced P2X7 models and docked three structurally distinct inhibitors using in silico approaches and show they have a similar mode of binding in which Phe95 plays a key role by forming pi-stacking interactions. Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity. This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity. Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | Adenosine triphosphate; AZ11645373; KN62; P2X7 receptor; SB203580 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 Jul 2015 12:05 |
Last Modified: | 01 Mar 2019 11:42 |
Published Version: | http://dx.doi.org/10.1016/j.bmcl.2015.06.001 |
Status: | Published |
Publisher: | Elsevier Ltd |
Identification Number: | 10.1016/j.bmcl.2015.06.001 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:88022 |