From three-dimensional GPCR structure to rational ligand discovery

Albert J. Kooistra, Rob Leurs, Iwan J.P. De Esch, Chris De Graaf*

*Corresponding author for this work
31 Citations (Scopus)

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.

Original languageEnglish
Title of host publicationG Protein-Coupled Receptors - Modeling and Simulation
Number of pages29
PublisherSpringer New York LLC
Publication date1 Jan 2014
Pages129-157
ISBN (Print)9789400774223
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes
SeriesAdvances in Experimental Medicine and Biology
Volume796
ISSN0065-2598

Keywords

  • Crystal structures
  • Docking
  • Drug design
  • In silico methods
  • Virtual screening

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