G Protein Coupled Receptors: Druggability and Structural Aspects

The 2012 Nobel in Chemistry was awarded to Robert Lefkowitz and Brian Kobilka for their scientific contributions in the inner-workings of G protein coupled receptor (GPCR) function. What culminated to this prestigious award was years of scientific endeavors by the above investigators and others towards understanding the structural basis of GPCR function. It is estimated 800 GPCRs are found in the human genome, which makes them one of the largest families in the proteome. Nevertheless, not all of them are potential drug targets. Specifically, 290 to 401 GPCRs could be amenable to therapeutic intervention, with about 46 of them having been targeted to date. Thus, there is still a significant number of GPCRs that could be related to human diseases. However, while there is no skepticism regarding the value of GPCRs as drug targets, the question is whether an activated receptor is always necessary for structure-based ligand (SBLD) discovery. In other words, is the existence of active state GPCR structures a prerequisite for a successful SBLD program?

GPCRs respond to a broad spectrum of extracellular signals, and depending on the signal they undergo conformational changes uponactivation. In turn, these changes are coupled to the activation of cytoplasmic G proteins, β-arrestins, and other effectors, thus inducing cascades of intracellular responses .