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

Zeng, HuangJiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China.;Jiaying Univ, Dept Pharm, Med Coll, Huangtang Rd 146, Meizhou 514031, Guangdong, Peoples R China. (author)

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.

Zhang, ShengyuanJiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China. (author)
Nie, HuaJiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China. (author)
Li, JunhaoUppsala universitet,Kemisk och biomolekylär fysik(Swepub:uu)jonli333 (author)
Yang, JiunlongJiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China. (author)
Zhuang, YuanbeiJiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China. (author)
Huang, YingjieJiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China. (author)
Zeng, MiaoJiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China. (author)
Jiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China.;Jiaying Univ, Dept Pharm, Med Coll, Huangtang Rd 146, Meizhou 514031, Guangdong, Peoples R China.Jiaying Univ, Inst Hakka Med Bioresources, Med Coll, Meizhou 514031, Peoples R China. (creator_code:org_t)

By the author/editor: Zeng, Huang; Zhang, Shengyuan; Nie, Hua; Li, Junhao; Yang, Jiunlong; Zhuang, Yuanbei; show more...; Huang, Yingjie; Zeng, Miao; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.