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

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7092-7100
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number19
DOIs
Publication statusPublished - 2010 Oct 1

Fingerprint

Tubulin Modulators
Tubulin
Screening
Colchicine
Cells
Microtubules
Cell Cycle Checkpoints
Polymerization
Cell Division
Podophyllotoxin
Lead compounds
Derivatives
G2 Phase
HL-60 Cells
Molecular modeling
Life Cycle Stages
Cytoskeleton
Cell Movement
Binding Sites
Life cycle

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Kim, Nam Doo ; Park, Eun Sook ; Kim, Young Hoon ; Moon, Seung Kee ; Lee, Sung Sook ; Ahn, Soon Kil ; Yu, Dae Yeul ; No, Kyoung Tai ; Kim, Kyun Hwan. / Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents. In: Bioorganic and Medicinal Chemistry. 2010 ; Vol. 18, No. 19. pp. 7092-7100.
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Structure-based virtual screening of novel tubulin inhibitors and their characterization as anti-mitotic agents. / Kim, Nam Doo; Park, Eun Sook; Kim, Young Hoon; Moon, Seung Kee; Lee, Sung Sook; Ahn, Soon Kil; Yu, Dae Yeul; No, Kyoung Tai; Kim, Kyun Hwan.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 19, 01.10.2010, p. 7092-7100.

Research output: Contribution to journalArticle

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