Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents |
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Authors: | Nam Doo Kim Eun-Sook Park Young Hoon Kim Seung Kee Moon Sung Sook Lee Soon Kil Ahn Dae-Yeul Yu Kyoung Tai No Kyun-Hwan Kim |
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Affiliation: | 1. Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea;2. Department of Pharmacology School of Medicine, and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University, Seoul 143-701, Republic of Korea;3. Research Institute of Medical Sciences, Konkuk University, Seoul 143-701, Republic of Korea;4. R&D Center, Equispharm Inc., Gyeonggi-do 443-766, Republic of Korea;5. CKD Research Institute, Chonan Post Office Box 74, Chonan 330-600, Republic of Korea;6. Department of Biology, College of Natural Science, Incheon University, Incheon 406-772, Republic of Korea;7. Aging Research Center, Korea Research Institute of Bioscience and Biotechnology 111 Gwahangno, Yuseong-gu Daejeon 305-806, Republic of Korea |
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Abstract: | 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. |
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