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KLIFS: A Knowledge-Based Structural Database To Navigate Kinase–Ligand Interaction Space

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Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
*Phone: +31-20598-7553. E-mail: [email protected]
Cite this: J. Med. Chem. 2014, 57, 2, 249–277
Publication Date (Web):August 13, 2013
https://doi.org/10.1021/jm400378w
Copyright © 2013 American Chemical Society
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    Abstract

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    Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase–ligand interactions in all regions of the catalytic cleft of all 1252 human kinase–ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase–ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase–ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.

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    2D structures of compounds that are not presented in other figures, a list of crystal structures of approved kinase inhibitors in the PDB, a table of all crystal structures used for the structural reference alignment, and the methodology of the KLIFS database preparation and analysis, including description of PDB collection, kinase domain sequence alignment, pocket selection, database creation, IFP generation, and DFG and αC-helix classification. This material is available free of charge via the Internet at http://pubs.acs.org. The KLIFS database is periodically updated and accessible on the Web at http://www.vu-compmedchem.nl, including all structure files and corresponding annotations.

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