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J Med Chem. 2016 May 12;59(9):4326-41. doi: 10.1021/acs.jmedchem.5b02041. Epub 2016 Mar 17.

Delineation of Polypharmacology across the Human Structural Kinome Using a Functional Site Interaction Fingerprint Approach.

Author information

1
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, Maryland 20894, United States.
2
Scripps Ranch , San Diego, California 92131, United States.
3
Department of Computer Science, Hunter College, The City University of New York , New York, New York 10065, United States.
4
The Graduate Center, The City University of New York , New York, New York 10016, United States.
5
Office of the Director, National Institutes of Health, Bethesda, Maryland 20892, United States.

Abstract

Targeted polypharmacology of kinases has emerged as a promising strategy to design efficient and safe therapeutics. Here, we perform a systematic study of kinase-ligand binding modes for the human structural kinome at scale (208 kinases, 1777 unique ligands, and their complexes) by integrating chemical genomics and structural genomics data and by introducing a functional site interaction fingerprint (Fs-IFP) method. New insights into kinase-ligand binding modes were obtained. We establish relationships between the features of binding modes, the ligands, and the binding pockets, respectively. We also drive the intrinsic binding specificity and which correlation with amino acid conservation. Third, we explore the landscape of the binding modes and highlight the regions of "selectivity pocket" and "selectivity entrance". Finally, we demonstrate that Fs-IFP similarity is directly correlated to the experimentally determined profile. These improve our understanding of kinase-ligand interactions and contribute to the design of novel polypharmacological therapies targeting kinases.

PMID:
26929980
PMCID:
PMC4865454
DOI:
10.1021/acs.jmedchem.5b02041
[Indexed for MEDLINE]
Free PMC Article

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