Identification of new IL-7Rα small-molecule agonists: a multi-computational approach

Interleukin 7 (IL-7) is an essential cytokine that acts as a potent growth factor of T-cells and supports the B-cell precursors. IL-7 binds to heterodimeric receptor consisting alpha (IL-7Rα) common gamma chain (γc) which shared with IL-2, IL-4, IL-9, IL-15 IL-21. The discovery small-molecule agonists cytokines would be great pharmaceutical interest increasing scientific rationale. In this study, series molecular modelling methods, including field-based pharmacophore virtual screening, protein-protein docking dynamics simulations, led identification two compounds (i.e. 1 2) different classes exhibit enhanced agonistic effects by activating signalling cascade. One these was selected hit represents first agonist IL-7Rα single-digit micromolar activity. Moreover, prediction model active compound IL-7Rα/γc interaction complex provides insight into binding its receptor.