Screening of Halogenated Flavonoids from Syzygium Species against PI3Kα for Breast Cancer

Abstract: Breast cancer is one of the leading causes of oncological mortality among women worldwide. Hyperactivation of the Phosphoinositide 3-kinase alpha (PI3Kα) signaling pathway plays a fundamental role in tumor cell proliferation, survival, metabolic reprogramming, and development of endocrine drug resistance, rendering it a highly sought-after therapeutic target. Natural flavonoids extracted from Syzygium species possess well-documented antioxidant and anti-proliferative capabilities; however, their synthetic modification via strategic halogenation offers a novel chemical space to potentially optimize binding affinities and pharmacokinetic behaviors. In the present work, a structure-based in silico molecular docking screening of several natural Syzygium flavonoids—including Luteolin derivatives (Luteolin 3-methyl ether, Luteolin 4-methyl ether, Luteolin 5-methyl ether, Luteolin 7-methyl ether, and 6-Methoxyluteolin) and Chrysin derivatives (Chrysin, Tectochrysin, 6,8-Dimethylchrysin, Chrysin 5,7-dimethyl ether, and Chrysin dimethyl ether)—alongside their prioritized halogenated analogues (6-bromo-luteolin and 3-iodochrysin) was carried out to evaluate their inhibitory potential against the ATP-binding pocket of the PI3Kα enzyme. Computational virtual screening was performed using AutoDock Vina, and the visualization of the precise macromolecular interaction pathways was evaluated with a visualizer tool. The binding affinity results were compared directly against Alpelisib, a standard synthetic clinically approved PI3Kα inhibitor. The halogenated derivatives (6-bromo-luteolin and 3-iodochrysin) exhibited exceptional binding energies that surpassed both their non-halogenated parent natural compounds and the standard drug, primarily due to the creation of stable, directional halogen bonds alongside conventional hydrogen-bonding cascades and aromatic $\pi$-stacking networks with key catalytic pocket residues (such as Val851 and Asp933). Keywords: Breast Cancer, PI3Kα Inhibitors, Syzygium Species, Halogenated Flavonoids, 6-Bromo-luteolin, 3-Iodochrysin, Molecular Docking, AutoDock Vina, Drug-Likeness, Virtual Screening.