Computational identification of candidate ST2-binding bioactive compounds as putative modulators for severe type...

This hypothesis-generating in silico screening study aimed to prioritize candidate ST2-binding bioactive compounds for severe Type 2-high asthma using an integrated workflow comprising molecular docking, protein-ligand interaction analysis, predicted ADMET profiling, molecular dynamics simulations, MM-GBSA binding-energy estimation, and density functional theory calculations. Sixteen compounds, including fifteen phytochemicals and one reference drug Zafirlukast, were screened against the ST2 receptor. Docking results indicated that several flavonoids, particularly Fisetin, Myricetin, Hesperetin, and Luteolin, showed more favorable predicted docking scores than the reference compound. Interaction analysis identified hydrogen-bonding and hydrophobic contacts with residues located within the selected ST2 binding pocket. Predicted ADMET profiling identified generally acceptable physicochemical and oral drug-likeness characteristics among the top-ranked compounds, although these predictions did not evaluate pulmonary delivery or inhalation pharmacokinetics. Among all candidates, Hesperetin was prioritized as a putative ST2-binding candidate based on its favorable predicted docking score, generally acceptable SwissADME profile, and recurring docking-derived interaction pattern within the selected ST2 pocket. Across three independently initialized molecular dynamics trajectories, the Hesperetin-ST2 complex showed dynamic persistence after an initial adjustment phase, whereas the Zafirlukast complex generally equilibrated earlier and exhibited lower RMSD values. Density functional theory analysis indicated a moderate HOMO-LUMO energy gap, providing supportive information on molecular reactivity and electronic stability. Hence, the findings prioritize Hesperetin for further experimental investigation as a candidate ST2-binding compound; however, receptor binding, functional IL-33/ST2 pathway inhibition, efficacy, and safety require validation through in vitro and in vivo studies.