Structure-based development of bitopic GPCR ligands showing functional selectivity at β-adrenergic receptors

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G protein-coupled receptors (GPCRs) are highly important pharmaceutical targets with multiple binding sites modulating their function. Apart from the orthosteric site, binding the native hormone/ neurotransmitter and an intracellular site recognizing a G protein or β-arrestin, allosteric binding sites located at the extracellular vestibule and the membrane-facing side of the receptor have been identified. Bitopic ligands are drugs or lead compounds comprising a pharmacophore for the orthosteric site and a second moiety specifically addressing an allosteric site. This project aims to design, synthesize and biologically investigate bitopic GPCR ligands based on an understanding of the structural and functional properties of each module and the impact of their ligation forming a bifunctional entity. The modules resulting from fragment-based virtual screening and chemical synthesis will be specifically functionalized and coupled, taking advantage of click chemistry. We will work on diffusible and covalently binding ligands. The computational compound design will be based on high-resolution structures (X-ray and cryo-EM structures) for a key player in cardiac physiology, the β-adrenergic receptor (βAR). Guided by docking, MD and FEP calculations, we will evolve bitopic lead compounds showing optimal complementarity and favorable interactions with two proximate receptor sites, the orthosteric binding pocket and the extracellular vestibule. Following a modular approach, we will probe synergistic or opposing properties between the two modules conferring the individual pharmacological profile of the bitopic ligands. Based on a structural understanding and cryo-EM structures of selected ligand-receptor complexes, the newly designed bitopic molecules will be optimized for their ability to activate the β2AR with Gi bias over Gs and β-arrestin.