Increasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?

Abstract

For years, conventional drug design at G-protein coupled receptors (GPCRs) has mainly focused on the inhibition of a single receptor at a usually well-defined ligand-binding site. The recent discovery of more and more physiologically relevant GPCR dimers/oligomers suggests that selectively targeting these complexes or designing small molecules that inhibit receptor-receptor interactions might provide new opportunities for novel drug discovery. To uncover the fundamental mechanisms and dynamics governing GPCR dimerization/oligomerization, it is crucial to understand the dynamic process of receptor-receptor association, and to identify regions that are suitable for selective drug binding. This minireview highlights current progress in the development of increasingly accurate dynamic molecular models of GPCR oligomers based on structural, biochemical, and biophysical information that has recently appeared in the literature. In view of this new information, there has never been a more exciting time for computational research into GPCRs than at present. Information-driven modern molecular models of GPCR complexes are expected to efficiently guide the rational design of GPCR oligomer-specific drugs, possibly allowing researchers to reach for the high-hanging fruits in GPCR drug discovery, i.e. more potent and selective drugs for efficient therapeutic interventions.

Figure 1. Structural comparison between representative class A GPCR crystal structures

Crystal structures of bovine rhodopsin (1GZM), squid rhodopsin (2ZIY), β2-adrenergic receptor (2RH1), β1-adrenergic receptor (2VT4), ligand-free bovine opsin (3CAP), and adenosine A2A receptor (3EML) are depicted in cyan, orange, blue, red, magenta, and grey colors, respectively. a) Global superposition of bovine rhodopsin, β2-adrenergic receptor, and β1-adrenergic receptor with regions exhibiting the largest conformational differences (EC2, IC2, and TM1) shown in cartoon representation; b) Global superposition of squid and bovine rhodopsin with TM5 and TM6 helices in cartoon representation; c) Global superposition (intracellular view) of bovine rhodopsin, ligand-free opsin, and adenosine A2A receptor with “ionic lock” residues E/D3.49, R3.50, and E6.30 in stick representation.

Figure 2. Alternative configurations of the TM4 interface of GPCR dimers

a) Simultaneous involvement of TM4 and TM5 at the dimerization interface; b) Exclusive involvement of TM4 at the dimerization interface.

Figure 3. Examples of small molecules targeting the TM region of GPCR heterodimers

(a) Bivalent ligands, i.e. molecules composed of two pharmacophores (green and magenta colors) covalently linked through a spacer (cyan connecting line); (b) Monovalent “drug-like” heterodimer-specific compounds (yellow color), and (c) Interface-disrupting compounds (cyan color).