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Impact of binding site waters on inhibitor design: contemplating a novel inverse binding mode of indirubin derivatives in DYRK kinases

DYRK kinases are involved in alternative pre-mRNA splicing as well as in neuropathological states such as Alzheimer's disease and Down syndrome. In this study, we present the design, synthesis, and biological evaluation of indirubins as DYRK inhibitors with enhanced selectivity. Modifications of the bis-indole included polar or acidic functionalities at positions 5′ and 6′ and a bromine or a trifluoromethyl group at position 7, affording analogues that possess high activity and pronounced specificity. Compound 6i carrying a 5′- carboxylate moiety demonstrated the best inhibitory profile. A novel inverse binding mode, which forms the basis for the improved selectivity, was suggested by molecular modeling and confirmed by determining the crystal structure of DYRK2 in complex with 6i. Structure–activity relationships were further established, including a thermodynamic analysis of binding site water molecules, offering a structural explanation for the selective DYRK inhibition [1].

References

  1. 1.

    Myrianthopoulos , et al: ACS Med Chem Lett. 2013, 4 (1): 22-26.

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Correspondence to Daniel Cappel.

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Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Keywords

  • Down Syndrome
  • Trifluoromethyl
  • Structural Explanation
  • Indirubin
  • Carboxylate Moiety