YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Binding Mode Studies of Indenoisoquinoline Analogues into Human Topoisomerase I-DNA Complex Using Flexible Docking

Human Topoisomerase I-DNA 절개가능 복합체에 대한 Indenoisoquinoline 유도체들의 결합양상 연구

  • Park, In-Seon (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Kim, Bo-Yeon (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Kim, Choon-Mi (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Choi, Sun (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University)
  • 박인선 (이화여자대학교 약학대학 대학원 생명.약학부) ;
  • 김보연 (이화여자대학교 약학대학 대학원 생명.약학부) ;
  • 김춘미 (이화여자대학교 약학대학 대학원 생명.약학부) ;
  • 최선 (이화여자대학교 약학대학 대학원 생명.약학부)
  • Published : 2009.08.31
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Abstract

Topoisomerase I (Topo I) participates in the DNA replication, transcription, and repair. Binding of Topo I inhibitor to the Topo I-DNA cleavage complex forms stabilized ternary complex which blocks DNA religation and ultimately causes cell death. Camptothecin (CPT) and its derivatives have been among the most effective anticancer drugs by inhibition of topo I. However, efforts to synthesize non-CPT drugs have been actively going on because the CPT derivatives have several limitations such as poor solubility, short half-life, and side effects. As an indenoisoquinoline, NSC314622 is not as potent as CPT, but its chemical stability and slower reversibility of the cleavage complex made it a good lead compound. Recently, a series of indenoisoquinoline analogues were synthesized with substituted dimethoxy or methylenedioxy on the aromatic ring and alkylamino on the lactam nitrogen. Some of them showed quite good Topo I inhibitory activity. Using the computer docking program, Surflex-Dock, indenoisoquinoline analogues were docked into the human Topo I-DNA cleavable complex. The docking results showed that the compounds with activity better than NSC314622 intercalated between the -1 and +1 base pairs at the cleavage site, but those with little or no activities did not appear to intercalate. These results could be useful to design new Topo I inhibitors improved than CPT.

Keywords

References

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