Identification of FTY720 and COH29 as novel topoisomerase I catalytic inhibitors by experimental and computational studies.

Autor: Zeng H; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China. Electronic address: zengh39@mail2.sysu.edu.cn., Zhang S; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China., Nie H; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China., Li J; Department of Physics and Astronomy, Uppsala University, Lägerhyddsvägen 1, SE-75121 Uppsala, Sweden., Yang J; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China., Zhuang Y; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China., Huang Y; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China., Zeng M; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Jun; Vol. 147, pp. 107412. Date of Electronic Publication: 2024 Apr 29.
DOI: 10.1016/j.bioorg.2024.107412
Abstrakt: The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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