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From Three-Dimensional GPCR Structure to Rational Ligand Discovery

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G Protein-Coupled Receptors - Modeling and Simulation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 796))

Abstract

This chapter will focus on G protein-coupled receptor structure-based virtual screening and ligand design. A generic virtual screening workflow and its individual elements will be introduced, covering amongst others the use of experimental data to steer the virtual screening process, ligand binding mode prediction, virtual screening for novel ligands, and rational structure-based virtual screening hit optimization. An overview of recent successful structure-based ligand discovery and design studies shows that receptor models, despite structural inaccuracies, can be efficiently used to find novel ligands for GPCRs. Moreover, the recently solved GPCR crystal structures have further increased the opportunities in structure-based ligand discovery for this pharmaceutically important protein family. The current chapter will discuss several challenges in rational ligand discovery based on GPCR structures including: (i) structure-based identification of ligands with specific effects on GPCR mediated signaling pathways, and (ii) virtual screening and structure-based optimization of fragment-like molecules.

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  1. Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands

    Albert J. Kooistra, Rob Leurs, Iwan J. P. de Esch & Chris de Graaf

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  1. Albert J. Kooistra
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  2. Rob Leurs
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  3. Iwan J. P. de Esch
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  4. Chris de Graaf
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Correspondence to Chris de Graaf .

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  1. Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York,, New York, USA

    Marta Filizola

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Kooistra, A.J., Leurs, R., de Esch, I.J.P., de Graaf, C. (2014). From Three-Dimensional GPCR Structure to Rational Ligand Discovery. In: Filizola, M. (eds) G Protein-Coupled Receptors - Modeling and Simulation. Advances in Experimental Medicine and Biology, vol 796. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7423-0_7

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