Anti-breast cancer effects of Pterocarpus soyauxii Taub aqueous extract and its compounds by integrating ADMET, network pharmacology, molecular docking, dynamic simulation, CLC-Pred and pdCSM-Cancer/PPI approaches, and in vitro validation

Abstract

Ethnopharmacological relevance: Breast cancer is one of the most common reasons women seek treatment at hospitals, and it has an exceptionally high mortality rate. Powder from the heartwood of Pterocarpus soyauxii Taub (P. soyauxii) is used in the department of Lékoumou in the Republic of the Congo (Congo-Brazzaville) in Central Africa to treat cancer.

Aim of the study: This exploratory study evaluated the anti-breast cancer effects of Pterocarpus soyauxii (P. soyauxii) compounds identified through the LC-MS in our recently published studies and its water extract.

Material and methods: The physicochemical, pharmacokinetic, and toxicological properties of these compounds were predicted via the MolSoft, AI-Druglab, ToxCSM, and SToPToX databases. Network pharmacology was conducted on both target proteins of breast cancer and P. soyauxii compounds via GeneCards, Metascape, STRING, and Cytoscape. Mapping of the signaling pathways involved in breast cancer and the PI3K/AKT/mTOR pathway was performed, and a KEGG pathway was constructed. A PPI network was established, and proteins with high scores were selected for molecular docking via Biovia and Molegro Virtual Docker software. The cytotoxic and proliferation-inhibitory capacities of breast cancer cell lines, as well as the proteins involved, were predicted using the CLC-Pred, way2drug, and pdCSM databases and in vitro assay.

Results: The results indicated that the compounds of P. soyauxii exhibited very low toxicity, were soluble in water, and were more than 30 % absorbable by the intestine, with a distribution greater than 2 L/kg and a half-life of less than 41.64 h. Network pharmacology and molecular docking revealed that the compounds interact with MAPK1 and CDK2, with respective energies lower than tamoxifen, at -87.03 mol/kcal and -125.66 mol/kcal for pterostilbene and linoleic acid. The compounds displayed cytotoxic and inhibitory effects on the proliferation of breast cancer cell lines, including MCF7 and MDA-MB-453, with a probability greater than 0.45 and a minimum GI₅₀ % of 4, which was weaker compared to tamoxifen. Additionally, the compounds exhibited antiestrogenic activity, with IC₅₀ values less than 5 Mole and Ki values greater than 5.50 Mole. Furthermore, the aqueous extract of P. soyauxii reduced the viability of MDA-MB-468 and MCF-7 cells less than tamoxifen, with IC₅₀s of 78.389 ± 0.0125 μg/mL and 58.389 ± 0.028 μg/mL, respectively.

Conclusion: These results suggest that P. soyauxii and its compounds have protective effects against various types of breast cancer by inhibiting the PI3K/AKT/mTOR pathway, which is essential for cell cycle progression and survival of cancer cells. However, in vivo experimental validation in models remains necessary to confirm this protective effect against breast cancer.

Keywords: ADMET; Breast cancer; Cytotoxicity; Dynamic simulation; In silico; Network pharmacology; P. soyauxii.