Drugging specific conformational states of GPCRs: challenges and opportunities for computational chemistry

•Structural evidence supports the existence of multiple GPCR conformations.•Conformational states coupling to unique transducers are attractive drug targets.•Computational structure-based methods can detect drugs binding such states.•Here, we analyze their potential and the challenges they still need to overcome.

Current advances in structural biology for membrane proteins support the existence of multiple Gprotein-coupled receptor (GPCR) conformations. These conformations can be associated to particular receptor states with definite coupling and signaling capacities. Drugging such receptor states represents an opportunity to discover a new generation of GPCR drugs with unprecedented specificity. However, exploiting recently available structural information to develop these drugs is still challenging. In this context, computational structure-based approaches can inform such drug development. In this review, we examine the potential of these approaches and the challenges they will need to overcome to guide the rational discovery of drugs targeting specific GPCR states.