Natural Phytochemicals from Macaranga conglomerata Brenan: A Cytotoxic and Computational Analysis against Cancer Targets

Cancer remains a significant global health challenge, necessitating the discovery of novel therapeutic agents from natural sources. This study explores the cytotoxic potential of phytochemicals extracted from the leaves of Macaranga conglomerata, focusing on five compounds: conglomeratin (1), macarangin (2), quercetin (3), 3,3′,4′-trimethoxyellagic acid (4), and 3,3′-dimethoxyellagic acid (5). The efficacy of compounds 1–5 was assessed against MCF-7 (breast cancer) and HepG2 (liver cancer) cell lines, with conglomeratin (1) demonstrating remarkable cytotoxicity, evidenced by IC₅₀ values of 16.2 and 13.1 μM, respectively. In contrast, compounds 2–5 exhibited moderate efficacy, with IC₅₀ values exceeding 50 μM, while doxorubicin, the reference drug, showed potent activity at 0.69 μM (MCF-7) and 0.81 μM (HepG2). To unravel the molecular basis of conglomeratin efficacy, advanced molecular modeling, including docking and dynamics simulations, was employed to investigate its interactions with epidermal growth factor receptor (EGFR) and cyclin-dependent kinase 2 (CDK2) key regulators of cancer cell proliferation. The results confirmed conglomeratin as a potent mixed multitarget inhibitor, engaging both proteins through a network of hydrogen bonds, hydrophobic interactions, and π–π stacking. These computational findings align with its superior in vitro cytotoxicity, positioning conglomeratin as a standout candidate among Macaranga-derived compounds for further development as an anticancer agent targeting human carcinomas.