G-protein-coupled receptors (GPCRs) are seven pass helical transmembrane receptors that regulate multiple cellular functions and therefore are also the largest class of drug targets. Upon binding to agonists, GPCRs mediate multiple signaling pathways by coupling to different intracellular transducer proteins such as G proteins and/or β-arrestins. Certain agonists exhibit bias in their efficacy to specific G-protein signaling pathways or β-arrestin mediated pathways. Such biased ligands provide precise therapeutic benefits with fewer side effects as drugs, compared to GPCR-targeted drugs available todate. The biased ligands elicit functional selectivity in GPCRs. There are very few biased ligands known for specific G-protein signaling pathways because designing biased agonists is a daunting experimental challenge. Additionally, there is a serious lack of understanding of structural information on how GPCRs modulate their functional selectivity for their cognate G-proteins or β-arrestins in cells. The functional selectivity of GPCRs stems from their dynamics and therefore requires techniques that probe into receptor dynamics to provide a structural basis for functional selectivity. In this talk I will outline the computational methods we have used to identify the allosteric communication pipelines from the extracellular ligand binding site to the intracellular part of the receptor where the transducer proteins couple. Based on the calculation of the allosteric pipelines from the extracellular loop residues to both the G-protein coupling site and arrestin coupling site we have recently developed a computational method to identify the “functional hotspot” residues in the agonist binding site that leads to ligand bias in a GPCR.I will show examples of these functional hotspot residues can be used to design biased ligands for GPCRs. <br/>

Using forward and backward allostery in GPCRs to drug design

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.