Computational Approach to Unveil Mechanisms of Action of Sesquiterpene Glycosides from Calendula officinalis against Gastric Cancer
DOI:
https://doi.org/10.53560/PPASA(63-1)709Keywords:
Anti-apoptosis, Calendula officinalis, Gastric Cancer, In Silico, Mcl-1, Sesquiterpene GlycosidesAbstract
Gastric cancer remains a major global health burden, and prognosis for advanced disease is frequently limited by late diagnosis and the toxicity of systemic chemotherapy. Mcl-1, an anti-apoptotic Bcl-2 family protein often overexpressed in gastric cancer, contributes to apoptosis evasion and treatment resistance, supporting its relevance as a therapeutic target. In this study, sesquiterpene glycosides from Calendula officinalis were evaluated as Mcl-1 (PDB: 6QFQ)-directed ligands using an integrated in silico workflow, with Etoposide as a reference. Docking identified CPD2 as the top-ranked compound (-10.75 kcal/mol), exceeding Etoposide (-9.80 kcal/mol), with a binding mode dominated by nonpolar contacts within the pocket and hydrogen-bond assignment to Arg263 and Leu267. During 100 ns molecular dynamics simulations, both complexes remained stable; CPD2 showed a RMSD values predominantly between 0.11–0.15 nm after equilibration and lower compactness/solvent-exposure trends (Rg 1.42-1.44 nm; SASA 82-88 nm²) relative to the Etoposide complex. MM/GBSA predicted a favorable association for both ligands, yielding comparable ΔTOTAL values (-28.72 ± 4.45 kcal/mol for CPD2; -29.80 ± 10.53 kcal/mol for Etoposide). ADMET prediction indicated high intestinal absorption for CPD2 (94.482%) despite low water solubility (-5.034 log mol/L), and DFT suggested greater electronic pliability for CPD2 (ΔE = 5.2502 eV) than Etoposide (ΔE = 11.1496 eV). Overall, CPD2 emerges as a prioritized computational hit for structure-guided optimization, and subsequent biochemical and cellular validation is expected to clarify its translational potential.
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