Drug platforms

Structural analyses of active, ligand-bound KOR could guide the design of biased KOR agonists to treat pain. A complex of crystallized KOR and a high-affinity ligand was suspended in a lipid-containing solution that used nanobodies to freeze the protein in its active state. Crystallographic analysis and computational modeling of the KOR-ligand complex identified hydrophobic interactions with residues W287 and Y312 that mediate the induction of arrestin β2 (ARRB2), which is responsible for side effects of unbiased KOR agonists. In silico drug design based on the findings, followed by chemical synthesis and testing in human kidney cell lines of the designed KOR agonists, yielded a compound that decreased activation of the ARRB2 pathway while retaining a bias for the receptor's G protein, compared with two full (unbiased) agonist tool compounds.

Next steps could include using the findings to design additional biased KOR agonists and testing them in pain models. ...