title: From three-dimensional GPCR structure to rational ligand discovery.
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.
authors.affiliation: 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.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
mesh_terms: D001665:Binding Sites; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled