Structure-first design of a photoswitchable JAK2 inhibitor candidate with isomer-selective binding.

Abstract

Precise control over kinase inhibitor selectivity and activity remains a central challenge in targeted drug design. While photopharmacology offers a route to modulate ligand activity with light, most implementations rely on azologization of existing scaffolds which limits the rational tuning of the structure-function relationships. Here, we present a de novo computational design strategy for a photoswitchable inhibitor candidate of Janus kinase 2 (JAK2), integrating molecular docking, molecular dynamics simulations, and binding free energy analysis to encode isomer-dependent affinity at the design stage. The resulting candidate ligand, IPTA, incorporates a photoresponsive core directly into the ligand architecture to achieve differential binding between its (E)- and (Z)-isomers. The (E)-isomer is predicted to form stable interactions with key regions of the JAK2 active site, including the hinge and xDFG motifs, whereas the (Z)-isomer exhibits reduced affinity due to steric incompatibility and loss of critical contacts. The free energy calculations predict a reversible, isomer-selective binding mechanism. Therefore, our work establishes a generalizable in silico framework for designing photoswitchable kinase inhibitor candidates with built-in functional asymmetry, highlighting the potential of computational approaches to guide photopharmacological ligand design.