ArticleJournal of chemical information and modeling2019
Smoothed Potential MD Simulations for Dissociation Kinetics of Etoposide To Unravel Isoform Specificity in Targeting Human Topoisomerase II.
Article in Journal of chemical information and modeling, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Structural insights into fungal and human topoisomerase II with implications for in silico antifungal drug design.Scientific reports · 2025Article
- Roles of Accelerated Molecular Dynamics Simulations in Predictions of Binding Kinetic Parameters.Mini reviews in medicinal chemistry · 2024Review
- Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer.Acta pharmaceutica Sinica. B · 2021Review
- Thermodynamics and Kinetics of Drug-Target Binding by Molecular Simulation.Chemical reviews · 2020Review
- Novel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β.Journal of medicinal chemistry · 2020Article
- Design, Synthesis, Dynamic Docking, Biochemical Characterization, andJournal of medicinal chemistry · 2020Article
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Authors and funding
3 authors.
Funding
Abstract
Human type II topoisomerases (TopoII) are essential for controlling DNA topology within the cell. For this reason, there are a number of TopoII-targeted anticancer drugs that act by inducing DNA cleavage mediated by both TopoII isoforms (TopoIIα and TopoIIβ) in cells. However, recent studies suggest that specific poisoning of TopoIIα may be a safer strategy for treating cancer. This is because poisoning of TopoIIβ appears to be linked to the generation of secondary leukemia in patients. We recently reported that enzyme-mediated DNA cleavage complexes (in which TopoII is covalently linked to the cleaved DNA during catalysis) formed in the presence of the anticancer drug etoposide persisted approximately 3-fold longer with TopoIIα than TopoIIβ. Notably, enhanced drug-target residence time may reduce the adverse effects of specific TopoIIα poisons. However, it is still not clear how to design drugs that are specific for the α isoform. In this study, we report the results of classical molecular dynamics (MD) simulations to comparatively analyze the molecular interactions formed within the TopoII/DNA/etoposide complex with both isoforms. We also used smoothed potential MD to estimate etoposide dissociation kinetics from the two isoform complexes. These extensive classical and enhanced sampling simulations revealed stabilizing interactions of etoposide with two serine residues (Ser763 and Ser800) in TopoIIα. These interactions are missing in TopoIIβ, where both amino acids are alanine residues. This may explain the greater persistence of etoposide-stabilized cleavage complexes formed with Topo TopoIIα. These findings could be useful for the rational design of specific TopoIIα poisons.
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