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Molecular Docking-assisted Protein Chip Screening of Inhibitors for Bcl-2 Family Protein-protein Interaction to Discover Anticancer Agents by Fragment-based Approach

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Abstract

For fragment-based cancer drug discovery, we introduced a molecular docking simulation combined with a protein chip assay. Protein chip technology was used to find fragment-hits that had inhibitory activity against Bcl-2 protein from 131 pre-selected fragment chemicals. Molecular docking simulation was performed for the 12 identified fragment-hits to establish the binding mode of these compounds in the Bcl-2 site. Using the molecular docking-assisted protein chip screening system, we derived a virtual compound structure with an important scaffold feature for interaction with the Bcl-2 protein. We then tested the anticancer activity of 26 compounds that were similar to the scaffold structure. The anticancer activity was confirmed by MTT-assay in A549 lung cancer cells. Finally, three chemicals showed dose-dependent inhibitory activity against cancer cell proliferation. We suggest that the present molecular docking-assisted protein chip assay can be used as a platform technology in the fragment-based drug development process to discover inhibitory agents of protein-protein interactions.

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1D1A3B03035796).

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Authors and Affiliations

  1. Department of Biomedical Laboratory, Korea Nazarene University, Cheonan, 31172, Korea

    Myoung-Schook Yoou

  2. School of Food and Pharmaceutical Engineering, Hoseo University, Asan, 31499, Korea

    Sungjoon Cho & Youngjin Choi

  3. Research Institute for Basic Science & BioChip Research Center, Hoseo University, Asan, 31499, Korea

    Youngjin Choi

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  1. Myoung-Schook Yoou
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  2. Sungjoon Cho
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Correspondence to Youngjin Choi.

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Molecular Docking-assisted Protein Chip Screening of Inhibitors for Bcl-2 Family Protein-protein Interaction to Discover Anticancer Agents by Fragment-based Approach

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Yoou, MS., Cho, S. & Choi, Y. Molecular Docking-assisted Protein Chip Screening of Inhibitors for Bcl-2 Family Protein-protein Interaction to Discover Anticancer Agents by Fragment-based Approach. BioChip J 13, 260–268 (2019). https://doi.org/10.1007/s13206-019-3306-4

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