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Binding mode analysis of topoisomerase inhibitors, 6-arylamino-7-chloro- quinazoline-5,8-diones, within the cleavable complex of human topoisomerase I and DNA

Title
Binding mode analysis of topoisomerase inhibitors, 6-arylamino-7-chloro- quinazoline-5,8-diones, within the cleavable complex of human topoisomerase I and DNA
Authors
Choi I.Kim C.Choi S.
Ewha Authors
김춘미최선
SCOPUS Author ID
김춘미scopus; 최선scopus
Issue Date
2007
Journal Title
Archives of Pharmacal Research
ISSN
0253-6269JCR Link
Citation
vol. 30, no. 12, pp. 1526 - 1535
Indexed
SCIE; SCOPUS; KCI WOS scopus
Abstract
A series of 6-arylamino-7-chloro-quinazoline-5,8-diones have been evaluated as novel human topoisomerase I (TOP1) inhibitors based on the antitumor activity of 1,4-naphthoquinone. Besides their in vitro cytotoxicity, their ability to inhibit human TOP1-DNA in vitro was tested with human TOP1 and a supercoiled (Form I) plasmid substrate DNA (Park et al., 2004). Using the flexible docking program, QXP, we have developed ternary complex models by docking camptothecin and ten 6-arylamino-7-chloro-quinazoline-5,8-dione analogs into the X-ray crystal structure of the human TOP1-DNA binary complex. The compound binding modes substantiated their potential inhibitory activities against TOP1 in the relaxation assay. Compounds whose templates the 6-arylamino-7-chloro-quinazoline-5,8-dione moiety intercalated between the -1 and +1 base pairs of the scissile strand showed good inhibitory activities. The template of compounds with poor inhibitory activities intercalated between the DNA base pairs of the nonscissile strand. The interaction of the compounds and the human TOP1-DNA binary complex were stabilized by an array of hydrogen bonds and hydrophobic interactions with the TOP1 residues, DNA bases, and water molecules. Docking results from the QXP program suggested potential binding modes of each non-CPT type compound in the human TOP1-DNA cleavable complex, which could provide a rational basis for future TOP1 inhibitor development.
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약학대학 > 약학과 > Journal papers
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