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

• 영문명: Binding Mode Studies of Indenoisoquinoline Analogues into Human Topoisomerase I-DNA Complex Using Flexible Docking
• 발행기관: 대한약학회
• 저자명: 박인선(In Seon Park) 김보연(Boyeon Kim) 김춘미(Choonmi Kim) 최선(Sun Choi)
• 간행물 정보: 『약학회지』제53권 제4호 (2009년), 228~234쪽, 전체 7쪽
• 주제분류: 의약학 > 기타의약학
• 파일형태: PDF
• 발행일자: 2009.08.31

영문 초록

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.1) 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.

키워드

topoisomerase Ⅰ-DNA complex indenoisoquinoline docking binding modes