Abstract
Theobroma cacao L. is a commercially important food/beverage and is used as traditional medicine worldwide against a variety of ailments. In the present study, computational biology approaches were implemented to elucidate the possible role of cocoa in cancer therapy. Bioactives of cocoa were retrieved from the PubChem database and queried for targets involved in cancer pathogenesis using BindingDB (similarity index ≥0.7). Later, the protein-protein interactions network was investigated using STRING and compound-protein via Cytoscape. In addition, intermolecular interactions were investigated via molecular docking. Also, the stability of the representative complex Hirsutrin-epidermal growth factor receptor (EGFR) complex was explored using molecular dynamics simulations. Crude extract metabolite profile was carried out by LC-MS. Further, anti-oxidant and cytotoxicity studies were performed in Chinese hamster ovary (normal) and Ehrlich ascites carcinoma (cancer) cell lines. Herein, the gene set enrichment and network analysis revealed 34 bioactives in cocoa targeting 50 proteins regulating 21 pathways involved in cancer and oxidative stress in humans. EGFR scored the highest edge count amongst 50 targets modulating 21 key pathways. Hence, it was selected as a promising anticancer target in this study. Structural refinement of EGFR was performed via all-atom molecular dynamics simulations in explicit solvent. A complex EGFR-Hirsutrin showed the least binding energy (-7.2 kcal/mol) and conserved non-bonded contacts with binding pocket residues. A stable complex formation of EGFR-Hirsutrin was observed during 100 ns MD simulation. In vitro studies corroborated antioxidant activity for cocoa extract and showed a significantly higher cytotoxic effect on cancer cells compared to normal cells. Our study virtually predicts anti-cancer activity for cocoa affected by hirsutrin inhibiting EGFR. Further wet-lab studies are needed to establish cocoa extract against cancer and oxidative stress.
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