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.

Background: Platelet-activating factor (PAF) is an agonist mediator in the inflammatory process, which interacts with PAF receptor (PAFR) that eventually causes cancers, respiratory and neurodegenerative diseases. This interaction activates the mitogen-activated protein kinase (MAPK) pathway, leading to a pro-inflammatory cascade. The pathophysiological conditions due to activation of inflammatory cascade could be inhibited by PAF antagonists. Objectives: In this study, selected naturally derived flavonoids (flavone, biochanin A, and myricetin) with different functional groups were subjected to molecular modelling and experimental studies to investigate their potential as PAF antagonists. Methods: Interactions of flavonoids and PAF were assessed via Autodock Vina for molecular docking and the AMBER program for molecular dynamic simulations. The experimentally antagonistic effects of the flavonoids were also conducted via PAF inhibitory assay to determine the IC50 values. Results: The findings of docking and dynamic simulations have revealed that all selected flavonoids interact with PAFR in the binding site with considerably good binding affinity up to - 9.8 kcal mol-1 as compared to cedrol (- 8.1 kcal mol-1) as a standard natural PAFR antagonist. The PAFR-flavonoid complexes exhibited four conserved active site residues, which included W73, F97, F174, and L279. The stability of all complexes was attained in a 30 ns simulation. The findings of in silico analyses were then compared to the experimental study on PAF inhibitory assay. Inhibitory effects of flavonoids against PAFR showed moderate activities, ranging from 27.8 – 30.8 μgM-1. Conclusion: All studied flavonoids could act as promising PAF antagonists with some enhancement in their structures to exhibit potent antagonistic activity. However, these naturally derived flavonoids demand further investigation at cellular and animal models to develop new PAF antagonist drug candidates for treating PAF-mediated diseases.