Volume 6 Supplement 1

9th German Conference on Chemoinformatics

Open Access

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

  • Daniel Cappel1Email author,
  • Vassilios Myrianthopoulos2,
  • Emmanuel Mikros2 and
  • Woody Sherman3
Journal of Cheminformatics20146(Suppl 1):P6

https://doi.org/10.1186/1758-2946-6-S1-P6

Published: 11 March 2014

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].

Authors’ Affiliations

(1)
Schrödinger GmbH
(2)
University of Athens, Panepistimiopolis Zografou
(3)
Schrödinger Inc.

References

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

Copyright

© Cappel et al; licensee Chemistry Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.