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Review
. 2016 Jan 15;26(2):241-250.
doi: 10.1016/j.bmcl.2015.12.024. Epub 2015 Dec 9.

Biased Agonism: An Emerging Paradigm in GPCR Drug Discovery

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Free PMC article
Review

Biased Agonism: An Emerging Paradigm in GPCR Drug Discovery

Zoran Rankovic et al. Bioorg Med Chem Lett. .
Free PMC article

Abstract

G protein coupled receptors have historically been one of the most druggable classes of cellular proteins. The members of this large receptor gene family couple to primary effectors, G proteins, that have built in mechanisms for regeneration and amplification of signaling with each engagement of receptor and ligand, a kinetic event in itself. In recent years GPCRs, have been found to interact with arrestin proteins to initiate signal propagation in the absence of G protein interactions. This pinnacle observation has changed a previously held notion of the linear spectrum of GPCR efficacy and uncovered a new paradigm in GPCR research and drug discovery that relies on multidimensionality of GPCR signaling. Ligands were found that selectively confer activity in one pathway over another, and this phenomenon has been referred to as 'biased agonism' or 'functional selectivity'. While great strides in the understanding of this phenomenon have been made in recent years, two critical questions still dominate the field: How can we rationally design biased GPCR ligands, and ultimately, which physiological responses are due to G protein versus arrestin interactions? This review will discuss the current understanding of some of the key aspects of biased signaling that are related to these questions, including mechanistic insights in the nature of biased signaling and methods for measuring ligand bias, as well as relevant examples of drug discovery applications and medicinal chemistry strategies that highlight the challenges and opportunities in this rapidly evolving field.

Keywords: Biased ligand; Drug discovery; Functional selectivity; GPCR.

Figures

Figure 1
Figure 1
Paradigms of GPCR-mediated signaling and multiple roles of βarrestins: binding of an agonist (a) results in activation of signaling pathways by G proteins (b), as well as βarrestins (f), in addition to desensitization and internalization by βarrestins (d and e).
Figure 2
Figure 2
βarrestin1 crystal structures. (a) Superimposed structures of βarrestin1 in a basal state (inactive state: blue; PDB 1G4 M) and in complex with V2Rpp (Vasopressin Receptor 2, partial protein, active state: green; PDB 4JQI) reveal marked conformational differences, including the release of the C-terminus which contains binding sites for partner proteins such as clathrin; (b) inactive state: the polar core consisting of five interacting residues keeping the C-terminus locked in the place is thought to be a critical stabilizer of the βarrestin1 inactive state (Arg393–Asp290 salt bridge highlighted by the broken black circle); (c) active state: upon V2Rpp binding (omitted for clarity) the C-terminal strand residue Arg393 is displaced, and its interacting partner Asp297 undergoes a large movement together with the rest of the lariat loop, resulting in significant conformational rearrangement in the polar core of the activated βarrestin1.
Figure 3
Figure 3
(a) Superimposed crystal structures of 5-HT1B (blue; PDB 4IAR) and 5HT2B (gold; PDB 4IB4) in complex with ergotamine (ERG); (b) prominent conformational difference of ERG bound to 5-HT1B (gray) and 5HT2B (green) is highlighted by the broken black circle. Contacts with additional residues observed in ERG-5HT2b structure are also highlighted (gold); (c) conserved DRY motif exist in an ‘active’ state (the Asp152–Arg153 salt bridge broken) in 5HT1B structure (blue), and ‘inactive’ state (the Asp146–Arg147 salt bridge intact) in 5HT2B structure (gold).
Figure 4
Figure 4
Aryl piperazine analogues of cariprazine and aripiprazole with different D2 receptor functional selectivity profiles.

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