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