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Current kinase inhibitors cover a tiny fraction of fragment space


Zhao, Hongtao; Caflisch, Amedeo (2015). Current kinase inhibitors cover a tiny fraction of fragment space. Bioorganic & Medicinal Chemistry Letters, 25(11):2372-2376.

Abstract

We analyze the chemical space coverage of kinase inhibitors in the public domain from a fragment point of view. A set of 26,668 kinase inhibitors from the ChEMBL database of bioactive molecules were decomposed automatically by fragmentation at rotatable bonds. Remarkably, about half of the resulting 10,302 fragments originate from inaccessible libraries, as they are not present in commercially available compounds. By mapping to the established kinase pharmacophore models, privileged fragments in sub-pockets are identified, for example, the 5681 ring-containing fragments capable of forming bi-dentate hydrogen bonds with the hinge region in the ATP binding site. Surprisingly, hinge-binding fragments in current kinase inhibitors cover only 1% of the potential hinge-binders obtained by decomposing a library of nearly 7.5 million commercially available compounds, which indicates that a large fraction of chemical space is unexplored.

Abstract

We analyze the chemical space coverage of kinase inhibitors in the public domain from a fragment point of view. A set of 26,668 kinase inhibitors from the ChEMBL database of bioactive molecules were decomposed automatically by fragmentation at rotatable bonds. Remarkably, about half of the resulting 10,302 fragments originate from inaccessible libraries, as they are not present in commercially available compounds. By mapping to the established kinase pharmacophore models, privileged fragments in sub-pockets are identified, for example, the 5681 ring-containing fragments capable of forming bi-dentate hydrogen bonds with the hinge region in the ATP binding site. Surprisingly, hinge-binding fragments in current kinase inhibitors cover only 1% of the potential hinge-binders obtained by decomposing a library of nearly 7.5 million commercially available compounds, which indicates that a large fraction of chemical space is unexplored.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:1 June 2015
Deposited On:24 Sep 2015 11:54
Last Modified:05 Apr 2016 19:25
Publisher:Elsevier
ISSN:0960-894X
Publisher DOI:https://doi.org/10.1016/j.bmcl.2015.04.005
PubMed ID:25911301

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