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Discovery of novel wee1 inhibitors via structure-based virtual screening and biological evaluation

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Abstract

Wee1 plays a critical role in the arrest of G2/M cell cycle for DNA repair before entering mitosis. Many cancer cells have been identified as overexpression of Wee1. In this research, pharmacophore modeling, molecular docking and molecular dynamics simulation approaches were constructed to identify novel potential Wee1 inhibitors. A compound 8 was found to have a novel skeleton against Wee1 with an IC50 value of 22.32 µM and a Ki value of 13.11 µM. Kinetic assays were employed to evaluate the compound 8 as a competitive inhibitor. Compound 8 was tested against A-549 tumor cell lines with IC50 value of 17.8 µM. To investigate the intermolecular interaction of Wee1 and compound 8, further molecular dynamics simulations were performed. It indicates that the binding mode of compound 8 and reference ligand is similar. The active core scaffold of compound 8 could represent a promising lead compound for studying Wee1 and be used for further structural optimization to design more potent Wee1 inhibitors.

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Acknowledgements

This work was financially supported by CAS “Light of West China” Program ([2014]91 to Z.Z.), CAS Strategic biological resources service network (ZSTH-021), the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDA12030206.

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Authors and Affiliations

  1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China

    Yaping Li, Yan Li & Zhili Zuo

  2. School of Chemical Engineering, Sichuan University of Science & Engineering, Zigong, 643000, Sichuan, China

    Yaping Li, Yinglan Pu, Hui Liu, Li Zhang, Xingyong Liu & Zhili Zuo

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  1. Yaping Li
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  2. Yinglan Pu
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Li, Y., Pu, Y., Liu, H. et al. Discovery of novel wee1 inhibitors via structure-based virtual screening and biological evaluation. J Comput Aided Mol Des 32, 901–915 (2018). https://doi.org/10.1007/s10822-018-0122-1

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