Structural characterization of Aurora kinase B modulation by Epigallocatechin gallate: Insights from docking and dynamics simulations.

Aurora Kinase B (AURKB) is crucial for chromosome alignment, segregation, and cytokinesis, phosphorylating essential proteins for accurate cell division. Mutations and overexpression of AURKB are common in various cancers. Inhibiting AURKB reduces therapy resistance, making it a promising therapeutic target. Synthetic inhibitors like AZD1152 and ZM447439 show selectivity for AURKB but often lack specificity due to high homology within the aurora kinase family. Conversely, natural molecules such as flavonoids offer selectivity, lower toxicity, and potential synergy with existing chemotherapies. Investigating natural AURKB inhibitors could lead to safer and more effective cancer treatments. Epigallocatechin-3-gallate (EGCG), a catechin ester in green tea, inhibits glioma cell line proliferation by inducing spontaneous apoptosis and reduces cancer cell invasiveness by decreasing metalloproteinase, cytokine, and chemokine activities. Additionally, EGCG inhibits several kinases, including PI3K, mTOR, EGFR, and AKT, acting as an effective ATP-competitive inhibitor. Thus, EGCG may enhance the efficacy of anti-cancer therapies as an AURKB inhibitor. This study used in silico tools to predict EGCG's pharmacodynamics and pharmacokinetics, and employed AutoDock for molecular docking with AURKB. The ligand-protein complex and Apo form of AURKB were simulated for 100 ns with GROMACS using the CHARM36 force field. Free energy surface analysis and MMPBSA methods confirmed the stability and spontaneity of EGCG binding to AURKB. The conformational dynamics of the DFG (Asp-Phe-Gly) motif in AURKB upon EGCG binding revealed significant changes crucial for ATP binding and kinase activity. The distance between the phenylalanine residue of the DFG motif and the αC helix in holo AURKB increased from 14.80 Å to 23.62 Å in the lowest free energy structure, indicating a shift from the DFG-in to the DFG-out state, affecting ATP binding. The study also noted transitions in the overall protein secondary structures, such as turn to coil, coil to sheet, and coil to helix, contributing to a stable structure upon EGCG binding. These findings highlight the complex interplay between EGCG and AURKB, providing insights into the conformational dynamics and structural alterations induced by this interaction, which has implications for reducing glioma cell chemosensitivity to therapeutic drugs.