Structure–dynamics analysis of insulin receptor modulation by plant-derived ligands suggests a potential regulatory role for Asn711

The insulin receptor (IR) is a central regulator of glucose homeostasis and represents a promising yet underexplored target for antidiabetic drug development. In this study, an integrated computational workflow combining large-scale phytochemical screening, molecular docking, and 200 ns molecular dynamics (MD) simulations was employed to identify plant-derived ligands capable of stabilizing activation-relevant regions of IR. From an initial library of 140 phytochemicals, Magnoflorine and Nerolidol emerged as top candidates based on binding affinity, ADMET properties, and interaction persistence. Docking results revealed favorable engagement of both ligands within the IR ectodomain, followed by MD simulations that confirmed stable complex formation and reduced structural fluctuations relative to the apo receptor. Both ligands showed stable interactions with Asn711, indicating that this residue may play a previously underappreciated role in ligand recognition. Dynamic analyses further demonstrated ligand mobility between the two insulin-binding sites, supporting a dual-site engagement mechanism analogous to insulin. Overall, these findings provide new mechanistic insights into IR modulation and suggest Magnoflorine and Nerolidol as promising lead molecules for the development of plant-based therapeutics targeting insulin resistance.