In-Silico Evaluation of Anti-Leukemic Potential of Selected Phytoconstituents from Withania Somnifera (L.)

Abstract

Introduction: Leukemia, a diverse group of hematological malignancies, poses a persistent clinical challenge despite advances in therapy. The exploration of natural products as anti-cancer agents has gained momentum, with Withania somnifera (L.) (Ashwagandha), a key Rasayana herb in Ayurveda, showing potential due to its rich phytochemical profile. Bioactive compounds from this plant exhibit antioxidant, immunomodulatory and cytotoxic properties, warranting investigation for anti-leukemic activity.
Methods: Eleven major phytoconstituents of Withania somnifera (L.) were evaluated against the therapeutic target Leukotriene A4 Hydrolase (LTA4H; PDB ID: 6TJU). Three-dimensional structures were retrieved from PubChem in SDF format only and prepared for docking. Molecular docking was performed using PyRx 0.8 (with the in-built AutoDock Vina engine) to assess binding energy, hydrogen bonding and RMSD. Pharmacokinetic profiling was performed using SwissADME to evaluate molecular weight, lipophilicity (iLogP), hydrogen-bond donors/acceptors and compliance with Lipinski's Rule of Five. Probable molecular targets were predicted using SwissTargetPrediction.
Results: Withanolide L demonstrated the strongest binding affinity (-9.8 kcal/mol) to LTA4H (6TJU), followed by Somniferanolide (-9.5 kcal/mol), Sominone (-9.4 kcal/mol), and Withanolide Q & R (-9.3 kcal/mol). All eleven compounds showed binding energies between -8.5 and -9.8 kcal/mol. Most compounds adhered to Lipinski's criteria with favourable ADME profiles. These results indicate the drug-likeness of these phytoconstituents and their ability to interact effectively with the active site of Leukotriene A4 Hydrolase (LTA4H).
Conclusion: The study highlights Withanolide L, Somniferanolide and Sominone as the most promising lead compounds for anti-leukemic drug development. Their strong binding affinities and favourable pharmacokinetic properties support further in vitro experimental validation. This study reinforces the therapeutic potential of Withania somnifera (L.) in hematological malignancies through computational drug discovery.