Discovery of Novel Bruton’s Tyrosine Kinase Inhibitors Using a Hybrid Protocol of Virtual Screening Approaches Based on SVM Model, Pharmacophore and Molecular Docking

Authors

  • Hua-Lin Wan,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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    • These authors contributed equally.

  • Ze-Rong Wang,

    1. West China School of Pharmacy, Sichuan University, Sichuan 610041, China
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    • These authors contributed equally.

  • Lin-Li Li,

    Corresponding author
    1. West China School of Pharmacy, Sichuan University, Sichuan 610041, China
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  • Chuan Cheng,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Pan Ji,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Jing-Jing Liu,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Hui Zhang,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Jun Zou,

    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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  • Sheng-Yong Yang

    Corresponding author
    1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China
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Corresponding authors: Sheng-Yong Yang, yangsy@scu.edu.cn; Lin-Li Li,ysylilinli@sina.com.cn

Abstract

Bruton’s tyrosine kinase has emerged as a potential target for the treatment for B-cell malignancies and autoimmune diseases. Discovery of Bruton’s tyrosine kinase inhibitors has thus attracted much attention recently. In this investigation, we introduced a hybrid protocol of virtual screening methods including support vector machine model-based virtual screening, pharmacophore model-based virtual screening and docking-based virtual screening for retrieving new Bruton’s tyrosine kinase inhibitors from commercially available chemical databases. Performances of the hybrid virtual screening approach were evaluated against a test set, which results showed that the hybrid virtual screening approach significantly shortened the overall screening time, and considerably increased the hit rate and enrichment factor compared with the individual method (SB-VS, PB-VS and DB-VS) or their combinations by twos. This hybrid virtual screening approach was then applied to screen several chemical databases including Specs (202 408 compounds) and Enamine (980 000 compounds) databases. Thirty-nine compounds were selected from the final hits and have been shifted to experimental studies.

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