article · Journal of Enzyme Inhibition and Medicinal Chemistry
Targeting human topoisomerase II is a recognised strategy in cancer treatment. Computational screening of over one hundred antibiotics evaluated their binding affinity to the topoisomerase II and DNA complex, followed by molecular dynamics simulations and binding energy calculations for the leading compounds. In laboratory testing across cancer cell lines, spiramycin and clarithromycin displayed promising antitumour effects against MCF-7 breast cancer cells, while clarithromycin and azithromycin showed positive activity against HCT-116 colon cancer cells. Direct enzymatic assays confirmed that erythromycin and roxithromycin act as potent topoisomerase II inhibitors. Structure-activity relationship analyses identified specific chemical features linked to these antitumour effects, demonstrating that several existing, commercially available macrolide antibiotics possess properties capable of inhibiting cancer-related molecular targets.
Repurposing existing medications offers an efficient pathway for discovering cancer therapies, as known drugs already have established manufacturing and safety profiles. Identifying that widely available macrolide antibiotics can target topoisomerase II and suppress cancer cell lines provides foundational insights for developing new oncology treatments or modifying existing molecular structures to improve antitumour performance.
This work points toward drug repurposing and oncology drug discovery applications for pharmaceutical developers and biotechnology firms. Because the findings are restricted to computational models, in vitro cell lines, and direct enzyme inhibition assays, the research remains at an early laboratory stage. Extensive preclinical validation, toxicity profiling, and animal studies would be required before any commercial clinical development could proceed.
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Topoisomerase II (TOP-2) is a promising molecular target for cancer therapy. Numerous antibiotics could interact with biologically relevant macromolecules and provoke antitumor potential. Herein, molecular docking studies were used to investigate the binding interactions of 138 antibiotics against the human topoisomerase II-DNA complex. Followed by the MD simulations for 200 ns and MM-GBSA calculations. On the other hand, the antitumor activities of the most promising candidates were investigated against three cancer cell lines using doxorubicin (DOX) as a reference drug. Notably, spiramycin (SP) and clarithromycin (CL) showed promising anticancer potentials on the MCF-7 cell line. Moreover, azithromycin (AZ) and CL exhibited good anticancer potentials against the HCT-116 cell line. Finally, the TOP-2 enzyme inhibition assay was carried out to confirm the proposed rationale. Briefly, potent TOP-2 inhibitory potentials were recorded for erythromycin (ER) and roxithromycin (RO). Additionally, a SAR study opened eyes to promising anticancer pharmacophores encountered by these antibiotics.HighlightsMolecular docking studies of 139 antibiotics against the topoisomerase II-DNA complex.SP, RO, AZ, CL, and ER were the most promising and commercially available candidates.Molecular dynamics simulations for 200 ns for the most promising five complexes.MM-GBSA calculations for the frontier five complexes.SP and CL showed promising anticancer potentials on the MCF-7 cell line, besides, AZ and CL exhibited good anticancer potentials against the HCT-116 cell line.Potent TOP-2 inhibitory potentials were recorded for ER and RO.
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DOI: 10.1080/14756366.2023.2171029
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