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Journal of the Korean Chemical Society (JKCS)

ISSN 1017-2548(Print)
ISSN 2234-8530(Online)
Volume 49, Number 5
JKCSEZ 49(5)
October 20, 2005 

Correlation between the Binding Mode and Inhibitory Activity of Benz[f]indole-4,9-dione Analogs with Human Topoisomerase I-DNA

Benz[f]indole-4,9-dione 유도체의 Topoisomerase I-DNA에 대한 결합형태와 저해작용 간의 상관관계
Inhee Choi, Suna Woo, Hae Sook Park, Hea-Young Park Choo, Choonmi Kim*

최인희, 우선아, 박혜숙, 박혜영, 김춘미*
Benz[f]indole-4,9-diones, Topoisomerase I, 결합형태, 저해작용, FlexiDock , Benz[f]indole-4,9-Diones, Topoisomerase I, Binding Mode, Inhibitory Activity, FlexiDock
새로 합성된 benz[f]indole-4,9-dione 유도체와 topoisomerase I(TOP1)-DNA 복합체의 결합형태를 규명하기 위해 세포독성과 TOP1 저해작용이 검사된 15개의 유도체와 camptothecin을 TOP1-DNA 복합체의 X-선 구조에 FlexiDock을 사용하여 docking하였다. 그 결과 N1에 할로겐이 결합된 두 화합물은 -1/+1 염기 사이에 끼어들어 깊숙이 결합되었고 각각 3개의 수소결합과 다수의 소수성 상호작용으로 안정화되었다. 활성검사에서 가장 강한 작용이 나타나 고유한 docking 결과와 잘 부합되었다. 염기사이에 끼어들지 않고 수소결합도 형성하지 않은 6개의 화합물에서는 활성이 거의 나타나지 않았다. 한 개 내지 4개의 수소 결합을 형성하면서 염기 사이에 끼어들었으나 TOP1에 의해 잘라지는 위치에 깊게 결합하지 못한 7개의 화합물은 중간 정도의 활성을 나타내어 구조-활성 관계가 실험 치와 잘 일치하였다. 이 결과는 TOP1을 목표로 하는 새로운 항암제의 구조를 고안하는데 합리적인 근거를 제공할 것이다.

We present binding modes of newly synthesized benz[f]indole-4,9-dione analogs with topoisomerase I (TOP1)-DNA complex. The compounds were tested for cytotoxicity and TOP1 inhibitory activity in our previous study. Camptothecin (CPT) and each of the 15 analogs were docked into the X-ray crystal structure of human TOP1-DNA binary complex to develop the ternary complex of TOP1-DNA-ligand using FlexiDock. The results demonstrated that two compounds with N1-attached halogens intercalated exactly between the -1 and +1 DNA bases, deeply toward the cleavage site and were stabilized by three H-bonds each and an array of hydrophobic interactions with both the enzyme and the DNA. The most potent inhibitory activities they showed in the test agree well with the proper docking results. Six compounds which did not intercalate and formed no H-bond showed no or very low inhibitory activities. Seven compounds that intercalated between the bases with one to four H-bonds but not deeply enough toward the cleavage site showed intermediate activities. The structure-activity relationship was consistent with the experimental data. The ternary complex presented potential binding mode of each compound and thus could provide a rational basis for novel inhibitor design to develop potent anticancer drugs targeting TOP1.

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