Abstract
Protein kinases are the second most prominent group of drug targets, after G-protein-coupled receptors. Despite their distinct inhibition mechanisms, the majority of kinase inhibitors engage the conserved hydrogen bond interactions with the backbone of hinge residues. We mined Pfizer internal crystal structure database (CSDb) comprising of several thousand of public as well as internal X-ray binary complexes to compile an inclusive list of hinge binding scaffolds. The minimum ring scaffolds with directly attached hetero-atoms and functional groups were extracted from the full compounds by applying a rule-based filtering procedure employing a comprehensive annotation of ATP-binding site of the human kinase complements. The results indicated large number of kinase inhibitors of diverse chemical structures are derived from a relatively small number of common scaffolds, which serve as the critical recognition elements for protein kinase interaction. Out of the nearly 4,000 kinase-inhibitor complexes in the CSDb we identified approximately 600 unique scaffolds. Hinge scaffolds are overwhelmingly flat with very little sp3 characteristics, and are less lipophilic than their corresponding parent compounds. Examples of the most common as well as the uncommon hinge scaffolds are presented. Although the most common scaffolds are found in complex with multiple kinase targets, a large number of them are uniquely bound to a specific kinase, suggesting certain scaffolds could be more promiscuous than the others. The compiled collection of hinge scaffolds along with their three-dimensional binding coordinates could serve as basis set for hinge hopping, a practice frequently employed to generate novel invention as well as to optimize existing leads in medicinal chemistry.
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Abbreviations
- KD:
-
Kinase domain
- CSDb:
-
Crystal structure database
- SAR:
-
Structure–activity relationship
- PSA:
-
Polar surface area
- 3D:
-
Three-dimension
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Acknowledgments
We thank Jacquelyn Mcleod-Klug for extracting kinase selectivity data and Gini coefficient, Kieth Burdick from Accelrys for technical support. We also thank the reviewers for their insightful suggestions. This study was sponsored by Pfizer Inc.
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10822_2013_9700_MOESM1_ESM.doc
Compilation of functional groups that were preserved as part of the hinge interacting ring systems, bar charts of number of crystal structures by kinase group and kinase family in CSDb, distribution of crystal structures on kinome dendrogram, hinge scaffolds of Fsp3 > 0.3, and hinge scaffolds along with their canonical smiles strings, number of binary complexes in the CSDb, number as well as names of different kinase targets. This material is available free of charge via the Internet at http://www.sciencedirect.com/. SD file of the unique hinge binding scaffolds are available upon request. (DOC 1,748 kb)
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Xing, L., Rai, B. & Lunney, E.A. Scaffold mining of kinase hinge binders in crystal structure database. J Comput Aided Mol Des 28, 13–23 (2014). https://doi.org/10.1007/s10822-013-9700-4
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DOI: https://doi.org/10.1007/s10822-013-9700-4