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Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations

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Abstract

Cdc25 phosphatase B, a potential target for cancer therapy, is inhibited by a series of quinones. The binding site and mode of quinone inhibitors to Cdc25B remains unclear, whereas this information is important for structure-based drug design. We investigated the potential binding site of NSC663284 [DA3003-1 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5, 8-dione] through docking and molecular dynamics simulations. Of the two main binding sites suggested by docking, the molecular dynamics simulations only support one site for stable binding of the inhibitor. Binding sites in and near the Cdc25B catalytic site that have been suggested previously do not lead to stable binding in 50 ns molecular dynamics (MD) simulations. In contrast, a shallow pocket between the C-terminal helix and the catalytic site provides a favourable binding site that shows high stability. Two similar binding modes featuring protein-inhibitor interactions involving Tyr428, Arg482, Thr547 and Ser549 are identified by clustering analysis of all stable MD trajectories. The relatively flexible C-terminal region of Cdc25B contributes to inhibitor binding. The binding mode of NSC663284, identified through MD simulation, likely prevents the binding of protein substrates to Cdc25B. The present results provide useful information for the design of quinone inhibitors and their mechanism of inhibition.

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Acknowledgements

The authors would like to thank Dr. C. J. Woods for helpful discussion and advice. YG and YL acknowledge financial support from National Science Found for Distinguished Young Scholars of China (21225313), Program for Changjiang Scholars and Innovative Research Team in University (IRT1030). Major State Special Research Project of China (2016YFA0101200), Major State Basic Research Development Program of China (973 Program, 2015CB553701), National Natural Science Foundation of China (NSFC, 21778050), Recruitment Program for Young Professionals (KJ2070000027). MWvdK and AJM thank BBSRC and EPSRC for support (EP/G007705/1; BB/L018756/1; BB/M026280).

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Author notes

  1. Yushu Ge and Marc van der Kamp have contributed equally to the work.

Authors and Affiliations

  1. School of Life Sciences, University of Science and Technology of China, Hefei, 230027, People’s Republic of China

    Yushu Ge & Dan Liu

  2. Centre of Computational Chemistry, School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK

    Yushu Ge, Marc van der Kamp, Maturos Malaisree & Adrian J. Mulholland

  3. School of Biochemistry, University of Bristol, Bristol, BS8 1TS, UK

    Marc van der Kamp

  4. State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education) & College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, People’s Republic of China

    Yi Liu

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  1. Yushu Ge
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  2. Marc van der Kamp
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  3. Maturos Malaisree
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  4. Dan Liu
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  5. Yi Liu
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Correspondence to Yushu Ge, Yi Liu or Adrian J. Mulholland.

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The work was performed at the Centre of Computational Chemistry, School of Chemistry, University of Bristol.

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Ge, Y., van der Kamp, M., Malaisree, M. et al. Identification of the quinolinedione inhibitor binding site in Cdc25 phosphatase B through docking and molecular dynamics simulations. J Comput Aided Mol Des 31, 995–1007 (2017). https://doi.org/10.1007/s10822-017-0073-y

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