Current kinase inhibitors cover a tiny fraction of fragment space.
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.
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: h.zhao@bioc.uzh.ch.
Hongtao
H
Zhao
Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.
Amedeo
A
Caflisch
D062126:Databases, Chemical; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries
Chemical space; Fragment-based drug discovery; Fragmentation; Kinase; Tricyclic ring systems