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J Chem Inf Model. 2015 Mar 23;55(3):538-49. doi: 10.1021/ci500624s. Epub 2015 Jan 20.

Pocketome of human kinases: prioritizing the ATP binding sites of (yet) untapped protein kinases for drug discovery.

Author information

1
†BioMed X Innovation Center, Im Neuenheimer Feld 583, 69120 Heidelberg, Germany.
2
‡Global Computational Chemistry, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.

Abstract

Protein kinases are involved in a variety of diseases including cancer, inflammation, and autoimmune disorders. Although the development of new kinase inhibitors is a major focus in pharmaceutical research, a large number of kinases remained so far unexplored in drug discovery projects. The selection and assessment of targets is an essential but challenging area. Today, a few thousands of experimentally determined kinase structures are available, covering about half of the human kinome. This large structural source allows guiding the target selection via structure-based druggability prediction approaches such as DoGSiteScorer. Here, a thorough analysis of the ATP pockets of the entire human kinome in the DFG-in state is presented in order to prioritize novel kinase structures for drug discovery projects. For this, all human kinase X-ray structures available in the PDB were collected, and homology models were generated for the missing part of the kinome. DoGSiteScorer was used to calculate geometrical and physicochemical properties of the ATP pockets and to predict the potential of each kinase to be druggable. The results indicate that about 75% of the kinome are in principle druggable. Top ranking structures comprise kinases that are primary targets of known approved drugs but additionally point to so far less explored kinases. The presented analysis provides new insights into the druggability of ATP binding pockets of the entire kinome. We anticipate this comprehensive druggability assessment of protein kinases to be helpful for the community to prioritize so far untapped kinases for drug discovery efforts.

PMID:
25557645
DOI:
10.1021/ci500624s
[Indexed for MEDLINE]

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