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From Three-Dimensional GPCR Structure to Rational Ligand Discovery

  • Albert J. Kooistra
  • Rob Leurs
  • Iwan J. P. de Esch
  • Chris de Graaf
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

Drug design In Silico methods Virtual screening Docking Crystal structures 

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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Albert J. Kooistra
    • 1
  • Rob Leurs
    • 1
  • Iwan J. P. de Esch
    • 1
  • Chris de Graaf
    • 1
  1. 1.Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)VU University AmsterdamAmsterdamThe Netherlands

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