Comparative Computational Evaluation of Flavonoid-Based Inhibitors Targeting Human TOP2A: Insights from Molecular Docking, Molecular Dynamics Simulation, and Binding Free Energy Analysis
Abstract
Abstract Prostate cancer (PCa) remains a major global health burden, particularly in its aggressive and treatment-resistant forms. Human topoisomerase IIα (TOP2A), a key regulator of DNA replication and cell proliferation, is significantly overexpressed in advanced prostate cancer and represents an important therapeutic target. In this study, a comprehensive computational pipeline was employed to evaluate phytocompounds derived from Dimocarpus longan as potential TOP2A inhibitors. A focused library of plant-derived compounds was screened using molecular docking, followed by pharmacokinetic and toxicity profiling via SwissADME and pkCSM. The top-ranked compounds were further subjected to 100 ns molecular dynamics (MD) simulations, along with MM/GBSA binding free energy calculations and principal component analysis (PCA), to assess their dynamic stability and interaction behavior. Among the screened compounds, luteolin, quercetin, and rutin demonstrated favorable binding affinities (− 10.4 to − 9.8 kcal/mol), outperforming the reference drug mitoxantrone. MD simulation results revealed stable protein–ligand interactions, with RMSD values below 3 Å and consistent structural compactness. Binding free energy analysis supported strong interaction profiles, particularly for luteolin and quercetin. ADMET predictions indicated acceptable pharmacokinetic properties and low toxicity risks. Overall, this study provides a detailed comparative analysis of flavonoid–TOP2A interactions,…
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Evidence Hub reads this as a preprint, done in computer models (in silico), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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