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Controlling the Dissociation of Ligands from the Adenosine A2A Receptor through Modulation of Salt Bridge Strength
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    Controlling the Dissociation of Ligands from the Adenosine A2A Receptor through Modulation of Salt Bridge Strength
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    Heptares Therapeutics Ltd, Biopark Broadwater Road, Welwyn Garden City AL7 3AX, U.K.
    Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University P.O. Box 9502, 2300 RA Leiden, the Netherlands
    *Dr. Robert M. Cooke. E-mail: [email protected]. Tel: +44 1707 358639.
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2016, 59, 13, 6470–6479
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    https://doi.org/10.1021/acs.jmedchem.6b00653
    Published June 17, 2016
    Copyright © 2016 American Chemical Society

    Abstract

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    The association and dissociation kinetics of ligands binding to proteins vary considerably, but the mechanisms behind this variability are poorly understood, limiting their utilization for drug discovery. This is particularly so for G protein-coupled receptors (GPCRs) where high resolution structural information is only beginning to emerge. Engineering the human A2A adenosine receptor has allowed structures to be solved in complex with the reference compound ZM241385 and four related ligands at high resolution. Differences between the structures are limited, with the most pronounced being the interaction of each ligand with a salt bridge on the extracellular side of the receptor. Mutagenesis experiments confirm the role of this salt bridge in controlling the dissociation kinetics of the ligands from the receptor, while molecular dynamics simulations demonstrate the ability of ligands to modulate salt bridge stability. These results shed light on a structural determinant of ligand dissociation kinetics and identify a means by which this property may be optimized.

    Copyright © 2016 American Chemical Society

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    • Free energy landscape plots from the metadynamics simulations for each ligand (PDF)

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    5IU4, A2A-StaR2-bRIL in complex with ZM241385; 5IU7, A2A-StaR2-bRIL in complex with 12c; 5IU8, A2A-StaR2-bRIL in complex with 12f; 5IUA, A2A-StaR2-bRIL in complex with 12b; 5IUB, A2A-StaR2-bRIL in complex with 12x. Authors will release the atomic coordinates upon article publication.

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    Cited By

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    This article is cited by 143 publications.

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    Cite this: J. Med. Chem. 2016, 59, 13, 6470–6479
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    https://doi.org/10.1021/acs.jmedchem.6b00653
    Published June 17, 2016
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