Acetogenins Exhibit Potential BCL-XL Inhibitor for the Induction of Apoptosis in the Molecular Docking Study.

BACKGROUND: Anti-apoptotic protein BCL-XL plays a vital role in tumorigenesis and cancer chemotherapy resistance, resulting in a good target for cancer treatment. Understanding the function of BCL-XL has driven the progression of a new class of cancer drugs that can mimic its natural inhibitors, BH3-only proteins, to trigger apoptosis. This mimicking is initiated through acetogenins due to their excellent biological properties. Acetogenins, which can be isolated from Annonaceae plants, have a unique structure along with several oxygenated functionalities. OBJECTIVE: Based on their biological capability, various acetogenins were studied in the present study and compared alongside ABT-737 on molecular docking. METHODS: The docking simulation of acetogenins was performed using AutoDock Vina software. RESULTS: Our findings have shown eleven acetogenins-BCL-XL protein complex, namely, muricin B (2), muricin F (4), muricin H (6), muricin I (7), xylomaticin (9), annomontacin (12), annonacin (14), squamocin (15), squamostatin A (16), bullatacin (20) and annoreticulin (21) exhibited strong binding affinities lower than - 10.4 kcalmol-1 as compared to ABT-373-BCL-XL complex. Six hydrogen bonds along with hydrophobic interaction were detected on the complex of BCL-XL with muricin B (2), muricin G (5), corossolone (11), and isoannonacin-10-one A (18). CONCLUSION: These findings indicated that some acetogenins could represent a new potential BCLXL inhibitor that could mimic the BH3-only protein for the induction of apoptosis in cancer chemotherapy.

Molecular Docking Study of Naturally Derived Flavonoids with Antiapoptotic BCL-2 and BCL-XL Proteins toward Ovarian Cancer Treatment.

The naturally derived flavonoids are well known to have anticarcinogenic effects. Flavonoids could be an alternative strategy for ovarian cancer treatment, due to existing platinum-based drugs are reported to develop resistance with low survival rates. Inhibition of antiapoptotic proteins, namely B-cell lymphoma (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl), is the key target to stimulate apoptosis process in cancer cells. This study aimed to determine the binding interaction of five naturally derived flavonoids (biochanin A, myricetin, apigenin, galangin, and fisetin) with potential antiapoptotic target proteins (Bcl-2 and Bcl-xl). The molecular docking study was conducted using AutoDock Vina program. The binding affinity and the presence of hydrogen bonds between the flavonoids and target proteins were predicted. Our findings showed that all the flavonoids showed better binding affinity with Bcl-xl than that of Bcl-2 proteins. The highest binding affinity was recorded in fisetin-Bcl-xl protein complex (-8.8 kcal/mol). Meanwhile, the other flavonoids docked with Bcl-xl protein showed binding affinities, ranging from -8.0 to -8.6 kcal/mol. A total of four hydrogen bonds, four hydrophobic contacts, and one electrostatic interaction were detected in the docked fisetin-Bcl-xl complex, explaining its high binding affinity with Bcl-xl. The present results indicate that all flavonoids could potentially serve as Bcl-xl protein inhibitors, which would consequently lead to apoptotic process in ovarian cancers.