Multisite Model of Allosterism for the Adenosine A1 Receptor

Giuseppe Deganutti; Kerry Barkan; Graham Ladds; Christopher A Reynolds

doi:10.1021/acs.jcim.0c01331

Multisite Model of Allosterism for the Adenosine A1 Receptor

Giuseppe Deganutti, Kerry Barkan, Graham Ladds, Christopher A Reynolds

University of Cambridge

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

120 Downloads (Pure)

Abstract

Despite being a target for about one-third of approved drugs, G protein-coupled receptors (GPCRs) still represent a tremendous reservoir for therapeutic strategies against diseases. For example, several cardiovascular and central nervous system conditions could benefit from clinical agents that activate the adenosine 1 receptor (A1R); however, the pursuit of A1R agonists for clinical use is usually impeded by both on- and off-target side effects. One of the possible strategies to overcome this issue is the development of positive allosteric modulators (PAMs) capable of selectively enhancing the effect of a specific receptor subtype and triggering functional selectivity (a phenomenon also referred to as bias). Intriguingly, besides enforcing the effect of agonists upon binding to an allosteric site, most of the A1R PAMs display intrinsic partial agonism and orthosteric competition with antagonists. To rationalize this behavior, we simulated the binding of the prototypical PAMs PD81723 and VCP171, the full-agonist NECA, the antagonist 13B, and the bitopic agonist VCP746. We propose that a single PAM can bind several A1R sites rather than a unique allosteric pocket, reconciling the structure-activity relationship and the mutagenesis results.

Original language	English
Pages (from-to)	2001-2015
Number of pages	15
Journal	Journal of Chemical Information and Modeling
Volume	61
Issue number	4
Early online date	29 Mar 2021
DOIs	https://doi.org/10.1021/acs.jcim.0c01331
Publication status	Published - 26 Apr 2021

Bibliographical note

Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

This document is the author’s post-print version, incorporating any revisions agreed during the peer-review process. Some differences between the published version and this version may remain and you are advised to consult the published version if you wish to cite from it.

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering
Computer Science Applications
Library and Information Sciences

Access to Document

10.1021/acs.jcim.0c01331

Post-PrintAccepted author manuscript, 4.05 MB
Deganutti_et-al_ci-2020-013319Accepted author manuscript, 65.3 MB

Cite this

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Multisite Model of Allosterism for the Adenosine A1 Receptor

Abstract

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