A Computational Investigation of Four Sesquiterpene [4+2] Trimers, Inubritantrimers A–D, and Their Synthetic Intermediates Isolated from Inula britannica L.

Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy with extremely limited effective targeted therapies. Natural products are promising alternatives for anticancer drug discovery, whereas integrated computational approaches serve as efficient tools for novel lead identification. Herein, four novel spiro-polycyclic sesquiterpene [4+2] trimers (Inubritantrimers A–D) and eight synthetic derivatives from Inula britannica L. were investigated via DFT calculations at the ωB97xD/6-311++G(2d,p) level (for geometric, electronic, spectral, and reactivity parameters), network pharmacology, molecular docking against seven core breast cancer-related targets, 500 ns all-atom molecular dynamics (MD) simulation, and MM/PBSA analysis. The results showed that the endo-type cycloaddition products had superior structural stability, with all reactions thermodynamically spontaneous (ΔG < 0). Compound 11 exhibited the most potent and balanced binding activity, with a docking free energy of −13.45 kcal/mol to MTOR; MD and MM/PBSA confirmed stable complex formation (total binding free energy −21.13 kcal/mol), driven predominantly by hydrophobic interactions. This study first established a comprehensive stereochemistry–electronic structure–property–activity relationship for this rare sesquiterpene trimer class and identified compound 11 as a promising MTOR-targeted TNBC lead. It provided a theoretical basis for developing high-efficiency, low-toxicity natural anticancer agents.