Modeling G protein-coupled receptors in complex with biased agonists

•A given GPCR structure can serve as the base to model other conformational states.•Modeling studies can explore conformational states globally or locally.•Virtual screening can be steered toward the retrieval of agonists or blockers.•Combining experimental and computational techniques might by the key to success.

The biological response to the activation of G protein-coupled receptors (GPCRs) typically originates from the simultaneous modulation of various signaling pathways that lead to distinct biological consequences. Hence, ‘biased agonists’ (i.e., compounds that selectively activate one of the pathways while blocking the others) are highly sought-after molecules to provide fine-tuned pharmacological interventions. This review describes strategies that can be deployed to model the conformation of GPCRs in complex with ligands endowed with specific signaling profiles useful for the generation of hypotheses on the structural requirements for the activation of different signaling pathways or for rational computer-aided ligand discovery campaigns. In particular, it focuses on strategies potentially applicable to model the global or local conformational states of GPCRs stabilized by specific ligands.