Predictive ADMET Assessment and Molecular Docking Analysis of Fisetin for Its Immunomodulatory Potential

Abstract

Background: Immune-mediated diseases impose substantial clinical and socioeconomic burdens, while prolonged use of conventional immunosuppressive agents may be associated with serious adverse effects. Fisetin, a naturally occurring flavonoid, has demonstrated anti-inflammatory and immunomodulatory properties, but its interaction with FK506-binding protein 12 (FKBP12) remains insufficiently characterised. Aim: This study aimed to evaluate the binding interaction of fisetin with FKBP12 and to assess its predicted absorption, distribution, metabolism, excretion, and toxicity properties in comparison with tacrolimus. Method: The three-dimensional structure of FKBP12 was prepared for molecular docking, while fisetin and tacrolimus were selected as ligands. Docking analysis was performed using AutoDock version 4.2.6. Drug-likeness, pharmacokinetic behaviour, and toxicity-related parameters were predicted using SwissADME and pkCSM. Results: Fisetin interacted with three FKBP12 binding sites, with predicted binding energies of −8.15, −7.92, and −5.62 kcal/mol. Tacrolimus showed corresponding binding energies of −10.29, −8.44, and −8.43 kcal/mol. Fisetin formed hydrogen-bond and hydrophobic interactions with several amino acid residues, including ARG18, GLU60, ALA64, PHE15, ARG13, and THR85. It showed no violation of Lipinski’s rule of five and had higher predicted gastrointestinal absorption than tacrolimus. No Ames toxicity, hERG inhibition, hepatotoxicity, or skin sensitisation was predicted for fisetin, although inhibition of CYP1A2, CYP2D6, and CYP3A4 was indicated. Conclusion: Fisetin demonstrated plausible binding to FKBP12 and a comparatively favourable predicted ADMET profile. These findings provide preliminary computational support for further investigation, although biochemical, cellular, and in vivo validation is required before its immunomodulatory potential can be confirmed.