Current kinase inhibitors cover a tiny fraction of fragment space

TitleCurrent kinase inhibitors cover a tiny fraction of fragment space
Publication TypeJournal Article
Year of Publication2015
AuthorsZhao H., Caflisch A.
JournalBioorganic & Medicinal Chemistry Letters
Start Page2372
Date PublishedJun 1, 2015
Type of ArticleResearch Article
KeywordsDrug Design, fragment-based docking, Kinase Inhibitors, Kinases, Small Molecule Libraries

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 7.5million commercially available compounds, which indicates that a large fraction of chemical space is unexplored.



Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID25911301
Highlight Role: 
Drug Design