GPCR drug discovery-moving beyond the orthosteric to the allosteric domain.

Allosteric modulation of G protein coupled receptors (GPCRs) is rapidly becoming a standard option for development of therapeutics headed to the clinic. Although GPCRs represent about 35% of marketed drugs, to date only two allosteric modulators have been approved for human use. However, many are now in early clinical development are can provide unique regulation of GPCRs including high selectivity along with physiologic temporal and spatial signaling. These molecules bind to a site that is distinct from the site where the endogenous agonist binds yet can provide robust modulation effects that span from the positive to the negative. Along with classical chemogenomic techniques, newer technology is being directly applied to their development including three dimensional biophysical structure-function analysis and in silico molecular dynamic simulations. The goal is to provide rationally designed molecules from well informed physical and in silico data to speed the discovery and development of the next generation therapeutics. In this chapter an example of the evolution of allosteric drug discovery targeting the muscarinic receptor family should serve to inform of progress in this exciting area of research and early drug development.