Allosteric Drugs for GPCR Oligomers by ESR5 Simone Mariani

GPCRs are a large family of transmembrane proteins representing a renowned target in drug discovery. Classical GPCR drugs are simply developed by targeting their orthosteric binding sites, yielding compounds that either activate or inactivate the protein. The main problem with this approach is that these sites are highly conserved among GPCR subfamilies, and this causes poor selectivity and possible side effects.
 
For this reason, in recent times the development of allosteric drugs, targeting GPCRs at sites that are different from the orthosteric binding sites, is getting increasingly relevant. The existence of such drugs has opened up the way for new therapeutic approaches and enriched the possible ways to modulate the functions of GPCRs1.
 
Many studies have underlined the importance of allosterism in the context of GPCR dimerization or higher-order oligomerization in the control of the physiological responses they modulate. Indeed, for many years, GPCRs have been studied as single functional units (i.e., monomers)1. However, recent evidence suggests that GPCRs can also work as higher-order oligomers constituted by equal (homo) or different (hetero) monomers.

Figure: Illustration of GPCRs in a dimeric state

In the case of oligomers, allosterism has a dual nature. On the one hand, a ligand alters the conformation of one monomer which then binds and modulates the configuration of the interacting receptor. On the other, the monomer itself can be considered as the allosteric modulator altering the conformation of the associated receptor, modulating its downstream efficacy and ligand affinity.
 
Therefore, GPCR oligomers have the potential to markedly expand the diversity and specificity of G protein-coupled receptor signaling, particularly in neural cells, where a few key receptors have been implicated in many neurological and psychiatric disorders, including addiction.
                       
Several approaches have been designed to develop new drugs specifically targeting GPCR dimers. One possible way is to design a so-called bivalent ligand 2, a molecule composed of two pharmacophores that span the length of the dimer allowing it to dock at both ligand binding sites simultaneously. An example of this was reported by Gmeiner et al. in 20163 with a study focused on targeting the D2R- NTS1R heteromer via three different bivalent ligands. In addition to this, it is also possible to develop bitopic ligands that bind the allosteric site of a monomer and simultaneously modulate the functions of the other associated functional unit. This is the case for instance of the SB269652 allosteric modulator of the Dopamine D2 dimer4.
 
 
 
 

1. D. Wootten, A. Christopoulos, P. M. Sexton, Emerging paradigms in GPCR allostery: implications for drug discovery, Nat Rev Drug Discov 12(8):630-44. (2013)
2. C. Hiller, J. Kühhorn,  P. Gmeiner, Class A G-Protein-Coupled Receptor (GPCR) Dimers and Bivalent Ligands, J. Med. Chem. 56 (17):6542–6559.  (2016)
3. H. Hübner, T. Schellhorn, M. Gienger, C. Schaab, J. Kaindl, L. Leeb, T. Clark, D. Möller,  P. Gmeiner, Structure-guided development of heterodimer-selective GPCR ligands, Nat. Commun. 7, 12298 (2016)
4. J. R. Lane, P. Donthamsetti, J. Shonberg, C. J. Draper-Joyce, S. Dentry, M. Michino, L. Shi, L. López, P. J. Scammells, B. Capuano, P. M. Sexton, J. A. Javitch, A. Christopoulos, A new mechanism of allostery in a G protein-coupled receptor dimer, Nat. Chem. Biol. 10:745–752 (2014)