Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents

被引:46
作者
Kim, Nam Doo [1 ,5 ]
Park, Eun-Sook [2 ,3 ,4 ]
Kim, Young Hoon [5 ]
Moon, Seung Kee [6 ]
Lee, Sung Sook [6 ]
Ahn, Soon Kil [7 ]
Yu, Dae-Yeul [8 ]
No, Kyoung Tai [1 ]
Kim, Kyun-Hwan [2 ,3 ,4 ]
机构
[1] Yonsei Univ, Dept Biotechnol, Coll Life Sci & Biotechnol, Seoul 120749, South Korea
[2] Konkuk Univ, Dept Pharmacol, Sch Med, Seoul 143701, South Korea
[3] Konkuk Univ, Ctr Canc Res & Diagnost Med, IBST, Seoul 143701, South Korea
[4] Konkuk Univ, Res Inst Med Sci, Seoul 143701, South Korea
[5] Equispharm Inc, R&D Ctr, Gyeonggi Do 443766, South Korea
[6] CKD Res Inst, Cheonan 330600, South Korea
[7] Incheon Univ, Dept Biol, Coll Nat Sci, Inchon 406772, South Korea
[8] Korea Res Inst Biosci & Biotechnol, Aging Res Ctr, Taejon 305806, South Korea
关键词
Microtubule; Colchicine; Virtual screening; Molecular docking; Pharmacophore; MICROTUBULE DYNAMICS; ANTIMITOTIC AGENTS; PHARMACOPHORE; COLCHICINE; RESISTANCE; INSIGHT; DOMAIN; DRUGS; POLYMERIZATION; IDENTIFICATION;
D O I
10.1016/j.bmc.2010.07.072
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Microtubule cytoskeletons are involved in many essential functions throughout the life cycle of cells, including transport of materials into cells, cell movement, and proper progression of cell division. Small compounds that can bind at the colchicine site of tubulin have drawn great attention because these agents can suppress or inhibit microtubule dynamics and tubulin polymerization. To find novel tubulin polymerization inhibitors as anti-mitotic agents, we performed a virtual screening study of the colchicine binding site on tubulin. Novel tubulin inhibitors were identified and characterized by their inhibitory activities on tubulin polymerization in vitro. The structural basis for the interaction of novel inhibitors with tubulin was investigated by molecular modeling, and we have proposed binding models for these hit compounds with tubulin. The proposed docking models were very similar to the binding pattern of colchicine or podophyllotoxin with tubulin. These new hit compound derivatives exerted growth inhibitory effects on the HL60 cell lines tested and exhibited strong cell cycle arrest at G2/M phase. Furthermore, these compounds induced apoptosis after cell cycle arrest. In this study, we show that the validated derivatives of compound 11 could serve as potent lead compounds for designing novel anti-cancer agents that target microtubules. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:7092 / 7100
页数:9
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