DFT and molecular modelling reveal the mechanism of action of selected alkaloids as anti-colorectal cancer agents targeting topoisomerase II

Colorectal cancer represents a significant cause of global mortality, necessitating the development of innovative therapeutic strategies with minimal toxicity. Alkaloids derived from medicinal plants demonstrate potential in cancer therapy by inhibiting cellular proliferation, promoting apoptosis, and altering vital signaling pathways. The present study investigated the mechanisms of alkaloids extracted from Tabernaemontana bovina as prospective agents against colorectal cancer, focusing on topoisomerase II (protein ID: 1ZXM), through network pharmacology and molecular modeling. Network pharmacology identified principal molecular targets and pathways, offering an integrated perspective on the biological effects of these alkaloids. Molecular docking demonstrated superior binding affinities for CPD4 relative to etoposide, implying enhanced capacity to regulate DNA topology. Molecular dynamics simulations over 100 ns validated consistent interactions, as evidenced by metrics including RMSD, RMSF, Rg, Hbonds, and SASA. MMGBSA analysis disclosed a more advantageous binding free energy for CPD4 (-18.12 kcal/mol) compared to etoposide (5.41 kcal/mol). DFT calculations highlighted distinct reactivity profiles, with CPD4 displaying higher HOMO energy (-5.825 eV) and a narrower energy gap (2.1057 eV) than etoposide (-8.3206 eV and 11.1496 eV), indicating greater electron donation and electrophilicity (10.8151 eV versus 0.6762 eV). In silico ADMET profiling revealed optimal gastrointestinal absorption, confined distribution, metabolism by CYP3A4, effective excretion, and absence of AMES toxicity. These outcomes designate CPD4 as a viable topoisomerase II inhibitor for colorectal cancer management. Furthermore, they provide a platform for synthesizing advanced analogs with augmented efficacy and safety, pending confirmation via in vitro and in vivo assays.