Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis.
MOTIVATION AND METHOD: Small-molecule inhibitors targeting the adenosine triphosphate (ATP) binding pocket of the catalytic domain of protein kinases have potential to become drugs devoid of (major) side effects, particularly if they bind selectively. Here, the sequences of the 518 human kinases are first mapped onto the structural alignment of 116 kinases of known three-dimensional structure. The multiple structure alignment is then used to encode the known strategies for developing selective inhibitors into a fingerprint. Finally, a network analysis is used to partition the kinases into clusters according to similarity of their fingerprints, i.e. physico-chemical characteristics of the residues responsible for selective binding.


RESULTS
For each kinase the network analysis reveals the likelihood to find selective inhibitors targeting the ATP binding site. Systematic guidelines are proposed to develop selective inhibitors. Importantly, the network analysis suggests that the tyrosine kinase EphB4 has high selectivity potential, which is consistent with the selectivity profile of two novel EphB4 inhibitors.


BACKGROUND
Supplementary data are available at Bioinformatics online.
Huang
Danzhi
D
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190. dhuang@bioc.uzh.ch
Zhou
Ting
T
Lafleur
Karine
K
Nevado
Cristina
C
Caflisch
Amedeo
A
D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D020539:Sequence Analysis, Protein / Q000379:methods; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases