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Two-track virtual screening approach to identify both competitive and allosteric inhibitors of human small C-terminal domain phosphatase 1

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Abstract

Despite a wealth of persuasive evidence for the involvement of human small C-terminal domain phosphatase 1 (Scp1) in the impairment of neuronal differentiation and in Huntington’s disease, small-molecule inhibitors of Scp1 have been rarely reported so far. This study aims to the discovery of both competitive and allosteric Scp1 inhibitors through the two-track virtual screening procedure. By virtue of the improvement of the scoring function by implementing a new molecular solvation energy term and by reoptimizing the atomic charges for the active-site Mg2+ ion cluster, we have been able to identify three allosteric and five competitive Scp1 inhibitors with low-micromolar inhibitory activity. Consistent with the results of kinetic studies on the inhibitory mechanisms, the allosteric inhibitors appear to be accommodated in the peripheral binding pocket through the hydrophobic interactions with the nonpolar residues whereas the competitive ones bind tightly in the active site with a direct coordination to the central Mg2+ ion. Some structural modifications to improve the biochemical potency of the newly identified inhibitors are proposed based on the binding modes estimated with docking simulations.

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Acknowledgements

This research was supported by BioNano Health-Guard Research Center funded by the Ministry of Science, ICT & Future Planning (MSIP) of Korea as Global Frontier Project (H-GUARD_2014M3A6B2060507) and by the Bio & Medical Technology Development Programs of the National Research Foundation, funded by the Korean Government (2015M3A9B5030308 and 2014M3A9B6070243).

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Authors and Affiliations

  1. Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul, 05006, South Korea

    Hwangseo Park

  2. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea

    Hye Seon Lee, Bonsu Ku & Seung Jun Kim

  3. National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Cheongwon-gu, Cheongju, 28116, South Korea

    Sang-Rae Lee

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  1. Hwangseo Park
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  2. Hye Seon Lee
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Correspondence to Hwangseo Park or Seung Jun Kim.

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Park, H., Lee, H.S., Ku, B. et al. Two-track virtual screening approach to identify both competitive and allosteric inhibitors of human small C-terminal domain phosphatase 1. J Comput Aided Mol Des 31, 743–753 (2017). https://doi.org/10.1007/s10822-017-0037-2

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  • DOI: https://doi.org/10.1007/s10822-017-0037-2

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