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Opportunities and Challenges in the Discovery of Allosteric Modulators of GPCRs

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Computational Methods for GPCR Drug Discovery

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

Abstract

From the pharmacological point of view, allosteric modulators may present numerous advantages over orthosteric ligands. Growing availability of novel tools and experimental data provides a tempting opportunity to apply computational methods to improve known modulators and design novel ones. However, recent progress in understanding of complexity of allostery increases awareness of problems involved in design of modulators with desired properties. Deeper insight into phenomena such as probe dependence, altering signaling bias with minor changes in ligand structure, as well as influence of subtle endogenous allosteric factors turns out to be fundamental. These effects make the design of a modulator with precise pharmacological outcome a very challenging task, and need to be taken into consideration throughout the design process. In this chapter, we focus on nuances of targeting GPCR allosteric sites in computational drug design efforts, in particular with application of docking, virtual screening, and molecular dynamics.

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Authors and Affiliations

  1. Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modelling Lab, Medical University of Lublin, 4A Chodźki Str., PL20093, Lublin, Poland

    Damian Bartuzi & Dariusz Matosiuk

  2. Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modelling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki Str., PL20093, Lublin, Poland

    Agnieszka A. Kaczor

  3. Department of Pharmaceutical Chemistry, School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211, Kuopio, Finland

    Agnieszka A. Kaczor

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  1. Damian Bartuzi
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  2. Agnieszka A. Kaczor
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  3. Dariusz Matosiuk
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Correspondence to Damian Bartuzi .

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

    Alexander Heifetz

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Bartuzi, D., Kaczor, A.A., Matosiuk, D. (2018). Opportunities and Challenges in the Discovery of Allosteric Modulators of GPCRs. 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_13

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  • DOI: https://doi.org/10.1007/978-1-4939-7465-8_13

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