Computational investigation of flavonoids from Dracaena steudneri Engl. as caspase-3 inducers in multidrug-resistant leukemia

Abstract

Leukemia is one of the most common forms of cancer worldwide, particularly in children. Multidrug-resistant leukemia remains a significant challenge in cancer therapy due to resistance mechanisms, including drug efflux pumps. Apoptosis, particularly via caspase-3 activation, is a key target to overcome this resistance. This study aimed to explore and assess the mechanisms of flavonoids CPD5, CPD7, and Doxorubicin as potential agents against multidrug-resistant leukemia. Key molecular targets identified include JNK1, AKT1, MAPK3, TP53, NFKB1, and CREB1, linked to apoptosis signaling. Molecular docking with the caspase-3 structure (PDB ID: 4JJE) revealed that CPD5 and Doxorubicin exhibited more stable binding energies and better localization within the protein 4JJE compared to CPD7. Molecular dynamics simulation over 100 ns confirmed stable binding interactions for all compounds. In silico ADMET predictions assessed oral bioavailability, showing CPD7 meets all pharmacokinetic criteria, being non-toxic, with superior distribution capacity and high absorption. These findings suggest CPD7 as a promising future drug for treating multidrug-resistant leukemia by inducing apoptosis through caspase-3 activation.