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

Yushu Ge*, Marc van der Kamp, Maturos Malaisree, Dan Liu, Yi Liu, Adrian J. Mulholland

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)
319 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)995-1007
Number of pages13
JournalJournal of Computer-Aided Molecular Design
Issue number11
Early online date9 Oct 2017
Publication statusPublished - 1 Nov 2017


  • NSC663284
  • Docking
  • Molecular dynamics
  • Binding mode
  • Protein flexibility


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