Introduction: DNA topoisomerases regulate DNA topology by creating transient single- or double-stranded breaks to relieve torsional stress during replication and transcription. Type II topoisomerase α (TOP۲A), predominantly expressed in proliferating cancer cells, functions as a homodimeric enzyme with four key domains: the ATP-binding motif, DNA gate, C-gate, and Mg²⁺/ATP-dependent catalytic domain. Inhibiting
TOP۲A triggers DNA damage and cell death, validating it as a cancer therapeutic target. Here, we investigated the potential of natural coumarins auraptene and galbanic acid to interact with the DNA-binding domain of
TOP۲A and suppress its activity against cancer cells. Methods: The crystal structure of human
TOP۲A was retrieved from the RCSB Protein Data Bank, and the three-dimensional SDF formats of auraptene and galbanic acid were obtained from PubChem.
Molecular docking was conducted using Proteins Plus. Ligands were treated flexibly to allow conformer generation and pose optimization. Docking parameters were set to high precision with a site radius of ۶.۵ Å, and JAMDA was employed as the docking algorithm. To visualize the interactions, PoseEdit was used to generate both ۲D and ۳D diagrams of the complexes, adhering to established chemical drawing conventions. Results: Docking analysis demonstrated favorable binding interactions of both ligands within the TOP۲A–DNA cleavage complex.
Auraptene showed a JAMDA docking score of −۱.۹۴۳ and formed a hydrogen bond with Met۷۶۲, while exhibiting van der Waals interactions with Glu۷۶۱ and Gly۷۶۰; additional hydrogen bonding with Glu۷۶۱ of the α and β chains was also observed.
Galbanic acid exhibited a JAMDA docking score of −۱.۵۸۵۳۳ and showed stable hydrogen bonding with Met۷۶۲ and van der Waals interactions with Glu۷۶۱ across the α chains, as well as interaction with Ser۸۰۲, a residue located within the catalytic region of TOP۲A. Conclusion: These findings position auraptene and galbanic acid as promising natural
TOP۲A inhibitors warranting further preclinical evaluation.
