YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Docking Studies of Camptothecin Analogues into Human Topoisomerase I-DNA Complex

Camptothecin 유도체의 Human Topoisomerase I-DNA 복합체에 대한 Docking 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

Human topoisomerase I (Topo I) plays a pivotal role in cell replication, transcription and repair and, therefore, is an important anti-cancer target. 20S-camptothecin (CPT) is a representative Topo I inhibitor. Compounds belonging to CPT family inhibit the religation step of Topo I-DNA by binding to the DNA cleavage site. Computational docking studies with Surflex-Dock were carried out to investigate the binding modes between Topo I-DNA binary complex structure and the ligand such as 20S-CPT and 9,10-substituted 20S-CPT analogues. The docking results demonstrated that most of the compounds with $IC_{50}$ value under $0.5{\mu}M$ intercalated exactly between the -1 and +1 DNA bases, deeply toward the cleavage site. The complex was stabilized by hydrogen-bonding and hydrophobic interactions with both the enzyme and the DNA. The compounds with $IC_{50}$ value above $0.5{\mu}M$ were poorly docked and did not intercalate. In addition, the docking results confirmed the overall correlation between the $IC_{50}$ values and docking scores, indicating the possible use of the modeling for the prediction of biological activity and design of potential inhibitors.

Keywords

References

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