Comparative in Silico Investigation of Costunolide and Dehydrocostus Lactone as Potential PTEN Modulators: DFT, Molecular Docking and Molecular Dynamics Approaches

Abstract

The phosphatase and tensin homolog (PTEN) is an important tumour suppressor that inhibits PI3 K/AKT/mTOR signalling pathway, which is generally dysregulated in malignancies. This study examined the potential regulatory effects of costunolide (COS) and dehydrocostus lactone (DEH) on PTEN through density functional theory (DFT), molecular docking, molecular dynamics (MD) simulations, and in silico pharmacokinetic analyses. DFT calculations revealed that both compounds possess strong electrophilic character, with COS showing higher chemical reactivity and DEH displaying greater stability. Molecular docking results indicated that both ligands bind favourably to PTEN active site. DEH has slightly stronger binding affinity (-7.6 kcal/mol) than COS (-7.3 kcal/mol). MD simulations demonstrated that PTEN-DEH complex maintained higher structural stability, compactness, and persistent hydrogen bonding compared to PTEN-COS complex, which exhibited greater fluctuations. However, MM/GBSA analysis revealed that COS had a better binding free energy (Delta G(bind) = -11.26 kcal/mol), suggesting a better balance between intermolecular interactions and solvation effects. ADME predictions confirmed favourable drug-likeness profiles and high gastrointestinal absorption for both ligands, adhering to Lipinski's rule of five. These findings suggest that both ligands are promising PTEN modulators; DEH exhibits superior structural stability, while COS displays more favourable binding energetics, providing a theoretical basis for further experimental validation in anticancer therapy.