Unveiling anti-apoptotic mechanisms of steroidal saponins from Dracaena draco L. in acute myeloid leukemia cells via in silico modeling

Abstract

Cancer, particularly acute myeloid leukemia, remains a critical global health challenge, necessitating innovative therapeutic strategies. In Chinese traditional medicine, the resin of Dracaena draco L. has been used for promoting blood circulation and alleviating stasis, and steroidal saponins isolated from this plant have shown cytotoxic potential against acute myeloid leukemia cells. However, their molecular mechanisms remain insufficiently defined. Given the pivotal role of BCL-2 mediated apoptosis regulation in acute myeloid leukemia pathogenesis, this study evaluated the anti-leukemic properties of selected steroidal saponins using computational approaches. Molecular docking demonstrated CPD1’s superior binding affinity (-10.93 kcal/mol) and favorable positioning within the 6GL8 binding pocket compared to venetoclax (-8.65 kcal/mol). Molecular dynamics simulations over 100 ns confirmed stable interactions underscoring CPD1’s capacity to modulate BCL-2 effectively. MMGBSA analysis revealed a more favorable binding free energy for CPD1-6GL8 (-56.13 kcal/mol) than venetoclax-6GL8 (-30.29 kcal/mol). ADMET profiling indicated CPD1’s non-genotoxicity, minimal hepatotoxicity, and balanced clearance, despite moderate intestinal absorption (55.034%) relative to venetoclax (100%). DFT analysis highlighted CPD1’s enhanced reactivity (ΔE = 2.8949 eV) compared to venetoclax (ΔE = 4.8522 eV), reflecting greater electrophilicity (13.8734 eV vs. 9.0166 eV). These results position CPD1 as a promising candidate for acute myeloid leukemia therapy through BCL-2-mediated anti-apoptosis.