In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Abstract

Signaling bias is a promising characteristic of G protein-coupled receptors (GPCRs) as it provides the opportunity to develop more efficacious and safer drugs. This is because biased ligands can avoid the activation of pathways linked to side effects whilst still producing the desired therapeutic effect. In this respect, a deeper understanding of receptor dynamics and implicated allosteric communication networks in signaling bias can accelerate the research on novel biased drug candidates. In this review, we aim to provide an overview of computational methods and techniques for studying allosteric communication and signaling bias in GPCRs. This includes (i) the detection of allosteric communication networks and (ii) the application of network theory for extracting relevant information pipelines and highly communicated sites in GPCRs. We focus on the most recent research and highlight structural insights obtained based on the framework of allosteric communication networks and network theory for GPCR signaling bias.

Essential Dynamics of CB1Receptor-Agonist Complexes: Implications for Signalling Bias

“…The latter residue has also been implicated in agonist bias. 41 The dihedral angle defining the Y397 rotamer of the N 7.49 P 7.50 xxY 7.53 motif ( Figure 10 , left ) was observed largely in a single state, in line with the recently reported CB1-βarrestin1 complex that noted the role of Y397, and the T210 3.46 , Y294 5.58 , Y397 7.53 triad polar network in recruiting βarr1. 42…”

Multiple triggers converge to preferential effector coupling in the CB2R through a complex allosteric communication network

“…Recent work provides evidence for the relevance of allosteric communication and implicated networks in GPCR function and signaling bias 10,11 . Allosteric communication networks (ACNs) serve as dynamic infrastructure that facilitates communication between remote regions within GPCRs, connecting critical sites like the ligand-binding site to the intracellular effector coupling site.…”