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Approaches for Differentiation and Interconverting GPCR Agonists and Antagonists

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Computational Methods for GPCR Drug Discovery

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1705))

Abstract

Predicting the functional preferences of the ligands was always a highly demanding task, much harder that predicting whether a ligand can bind to the receptor. This is because of significant similarities of agonists, antagonists and inverse agonists which are binding usually in the same binding site of the receptor and only small structural changes can push receptor toward a particular activation state. For G protein-coupled receptors, due to a large progress in crystallization techniques and also in receptor thermal stabilization, it was possible to obtain a large number of high-quality structures of complexes of these receptors with agonists and non-agonists. Additionally, the long-time-scale molecular dynamics simulations revealed how the activation processes of GPCRs can take place. Using both theoretical and experimental knowledge it was possible to employ many clever and sophisticated methods which can help to differentiate agonists and non-agonists, so one can interconvert them in search of the optimal drug.

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Acknowledgments

Figure 3 is reproduced from J. Chem. Inf. Model. 2015 (http://pubs.acs.org/doi/full/10.1021/acs.jcim.5b00066) with permission from American Chemical Society. Figure 9 is reproduced from ACS Chem. Biol. 2013 (http://pubs.acs.org/doi/full/10.1021/cb400103f) with permission from American Chemical Society. Figure 18 is reproduced from FEBS Lett. 2015 with permission from John Wiley and Sons.

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Authors and Affiliations

  1. Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093, Warsaw, Poland

    Przemysław Miszta, Jakub Jakowiecki, Ewelina Rutkowska, Maria Turant, Dorota Latek & Sławomir Filipek

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  1. Przemysław Miszta
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  2. Jakub Jakowiecki
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  3. Ewelina Rutkowska
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  4. Maria Turant
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  5. Dorota Latek
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  6. Sławomir Filipek
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Correspondence to Sławomir Filipek .

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  1. Evotec (UK) Ltd., Abingdon, Oxfordshire, United Kingdom

    Alexander Heifetz

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Miszta, P., Jakowiecki, J., Rutkowska, E., Turant, M., Latek, D., Filipek, S. (2018). Approaches for Differentiation and Interconverting GPCR Agonists and Antagonists. In: Heifetz, A. (eds) Computational Methods for GPCR Drug Discovery. Methods in Molecular Biology, vol 1705. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7465-8_12

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  • DOI: https://doi.org/10.1007/978-1-4939-7465-8_12

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