From G Protein-coupled Receptor Structure Resolution to Rational Drug Design

Abstract A number of recent technical solutions have led to significant advances in G protein-coupled receptors structural biology. Apart from detailed mechanistic view of receptor activation, the new receptor structures have revealed novel and unexpected ligand binding sites. Together, these sets of insights provide exciting avenues for medicinal chemists to rationally design new molecular entities to modulate the activities of these proteins which belong to one of the most important classes of drug targets. Application of structure based drug design methodologies to GPCRs ushers in an exciting era with the potential of not only improving on existing drugs but also discovering new drugs to previously challenging yet clinically validated targets. In this review we focus on technical solutions that have accelerated GPCR crystallography as well as some of the salient learnings from structures that are relevant to drug discovery. Finally we will outline some of the approaches used in GPCR structure based drug design.