4.26 – Seven Transmembrane G Protein-Coupled Receptors: Insights for Drug Design from Structure and Modeling

This chapter describes modeling techniques that have been reported for the design of G protein-complex receptor (GPCR) ligands, summarizing the success of key methodologies and the targets to which they have been applied. The discussion focuses mainly on the building of GPCR models and their use in structure-based ligand design, although a summary of key ligand-based methods is also included. The first section describes the model building process. The history of receptor modeling and the data on which it is based are reported, explaining how modeling techniques and the resulting models have evolved as the quality and quantity of underlying experimental studies have increased. Both homology modeling and de novo model-building methods are covered. Current challenges and aims for the future are also discussed with particular focus on modeling of activated receptor states and Family B and C GPCRs. The focus of the chapter then moves to the utilization of these models for drug design. Firstly design techniques based on the docking of small numbers of ligands into receptor models are discussed. Then the challenging topic of combining high-throughput docking techniques with receptor models is tackled. Finally, an attempt is made to summarize the wealth of small-molecule modeling methods that have been reported in the literature. Particular attention is paid to methods for selecting compound sets enriched in GPCR ligands which encompass library design. Due to the immensity of that task and the fact that ligand-based methods are discussed in detail elsewhere in this book, the emphasis in this chapter is on those methods that either have special relevance to GPCR ligands, or those that have been shown to be particularly successful when applied to the area.