From heptahelical bundle to hits from the Haystack: structure-based virtual screening for GPCR ligands

Abstract

This review will focus on the construction, refinement, and validation of G-protein-coupled receptor (GPCR) structural models for the purpose of structure-based virtual screening (SBVS) and ligand design. The review will present a comparative analysis of GPCR crystal structures and their implication on GPCR (homology) modeling. The challenges associated with steps along the modeling workflow will be discussed: the use of experimental anchors to steer the modeling procedure, amino acid sequence alignment and template selection, receptor structure refinement, loop modeling, ligand-binding mode prediction, and virtual screening for novel ligands. An overview of several 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.