New technologies enabling the industrialization of allosteric modulator discovery

Novel Screening Paradigms for the Identification of Allosteric Modulators and/or Biased Ligands for Challenging G-Protein-Coupled Receptors

“…They yield information about the AM cooperativity factor-α, a parameter quantifying the influence of the AM on the binding of the orthosteric probe. With the second one, PAM or NAM activity of the test compound is assessed in the presence of an EC [10][11][12][13][14][15][16][17][18][19][20] or EC 80 concentration of a known (preferably endogenous) agonist, respectively. However, these radioactive binding assays should be used with caution as NAMs with high negative α values could be mistaken as competitive orthosteric ligands, and in many cases, AMs can influence signaling with no detectable effect on ligand binding.…”