The Best of Both Worlds? Bitopic Orthosteric/Allosteric Ligands of G Protein–Coupled Receptors

Abstract

It is now acknowledged that G protein-coupled receptors, the largest class of drug targets, adopt multiple active states that can be preferentially stabilized by orthosteric ligands or allosteric modulators, thus giving rise to the phenomenon of pathway-biased signaling. In the past few years, researchers have begun to explore the potential of linking orthosteric and allosteric pharmacophores to yield bitopic hybrid ligands. This approach is an extension of the more traditional bivalent ligand concept and shares some of the same challenges, including the choice and role of the linker between the two pharmacophores and the validation of mechanism of action. Nonetheless, the promise of bitopic ligands is the generation of novel chemical tools that have improved affinity and/or selectivity profiles. Previously identified functionally selective compounds (and medicines) also may act via a bitopic mechanism, suggesting that the phenomenon is more widespread than currently appreciated.

Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46

“…Recent insights into mechanisms for regulating signaling by GPCRs emphasize the complexities associated with biased agonism and allosteric modulation. [36][37][38][39] Emerging structural and pharmacologic information supports the notion that GPCRs exist in dynamic conformational ensembles and that agonists, biased agonists, or allosteric ligands stabilize 1 or more conformational subsets at the expense of others with functional consequences and highly selective signaling outcomes. 36,[40][41][42][43][44][45] Proteolysis at Arg41 versus at Arg46 de facto alters the spectrum of conformations of PAR1 because of differences in sequence and N-terminus after cleavage at either Arg41 or Arg46.…”

Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist

“…Recent studies have highlighted both the attractive potential of linking orthosteric and allosteric pharmacophores and the challenges associated with the development of such ligands (25,26). Ideally, an optimal bitopic ligand should display improved affinity relative to its individual orthosteric and allosteric pharmacophores.…”

“…(ii) If the orthosteric site is already occupied (e.g., in the presence of very high concentrations of orthosteric antagonist), then the bitopic ligand may adopt a different, lower-affinity orientation using only the allosteric site and thus, allow an allosteric interaction between the two molecules to occur (24)(25)(26)30). If the allosteric moiety displays agonism, then the additional potential exists for a noncompetitive interaction when the ligands are interacting allosterically.…”

GPCRs through the keyhole: the role of protein flexibility in ligand binding to β-adrenoceptors

“…Thus our docking findings suggest a possible novel binding mode for bivalent ligands. Valant, Robert Lane, Sexton, & Christopoulos, 2012) The keyhole hypothesis does not provide a complete rationalisation of the 1-AR selectivity for all extended ligands, as both 1-and 2-AR subtypes appear capable of producing this feature. However there are subtle differences between subtypes in the geometry and chemical composition of the keyhole due to the non-conserved this region more similar to those in 1-AR .…”