Generation of ligand-based pharmacophore model and virtual screening for identification of novel tubulin inhibitors with potent anticancer activity

Yi Kun Chiang, Ching Chuan Kuo, Yu Shan Wu, Chung Tong Chen, Mohane Selvaraj Coumar, Jian Sung Wu, Hsing Pang Hsieh, Chi Yen Chang, Huan Yi Jseng, Ming Hsine Wu, Jiun Shyang Leou, Jen Shin Song, Jang Yang Chang, Ping Chiang Lyu, Yu Sheng Chao, Su Ying Wu

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Abstract

A pharmacophore model, Hypo1, was built on the basis of 21 training-set indole compounds with varying levels of antiproliferative activity. Hypo1 possessed important chemical features required for the inhibitors and demonstrated good predictive ability for biological activity, with high correlation coefficients of 0.96 and 0.89 for the training-set and test-set compounds, respectively. Further utilization of the Hypo1 pharmacophore model to screen chemical database in silico led to the identification of four compounds with antiproliferative activity. Among these four compounds, 43 showed potent antiproliferative activity against various cancer cell lines with the strongest inhibition on the proliferation of KB cells (IC50 = 187 nM). Further biological characterization revealed that 43 effectively inhibited tubulin polymerization and significantly induced cell cycle arrest in G2-M phase. In addition, 43 also showed the in vivo-like anticancer effects. To our knowledge, 43 is the most potent antiproliferative compound with antitubulin activity discovered by computer-aided drug design. The chemical novelty of 43 and its anticancer activities make this compound worthy of further lead optimization.

Original languageEnglish
Pages (from-to)4221-4233
Number of pages13
JournalJournal of Medicinal Chemistry
Volume52
Issue number14
DOIs
Publication statusPublished - 2009 Jul 23

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Chiang, Y. K., Kuo, C. C., Wu, Y. S., Chen, C. T., Coumar, M. S., Wu, J. S., Hsieh, H. P., Chang, C. Y., Jseng, H. Y., Wu, M. H., Leou, J. S., Song, J. S., Chang, J. Y., Lyu, P. C., Chao, Y. S., & Wu, S. Y. (2009). Generation of ligand-based pharmacophore model and virtual screening for identification of novel tubulin inhibitors with potent anticancer activity. Journal of Medicinal Chemistry, 52(14), 4221-4233. https://doi.org/10.1021/jm801649y