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A Role for Hydration in Interleukin‐2 Inducible T Cell Kinase (Itk) Selectivity
Author(s) -
Knegtel Ronald M. A.,
Robinson Daniel D.
Publication year - 2011
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201100086
Subject(s) - selectivity , chemistry , active site , enzyme , kinase , molecular dynamics , residue (chemistry) , binding site , ligand (biochemistry) , stereochemistry , combinatorial chemistry , computational chemistry , biochemistry , receptor , catalysis
The selectivity profile of kinase inhibitors is commonly explained in terms of favourable or unfavourable interactions between the inhibitor and active site residues. In practice residue sequence differences have not always been sufficient to explain observed selectivity profiles. A series of interleukin‐2 inducible T cell kinase (Itk, EC 2.7.10.2) inhibitors that achieve selectivity through the introduction of a single nitrogen atom in an aromatic ring has recently been discovered. Structures of these inhibitors bound to Itk showed this nitrogen to be solvent exposed and not involved in any direct interactions with the enzyme. By analysing active site hydration, using the molecular dynamics tool WaterMap, the observed selectivity profile can be explained in terms of the replacement of a thermodynamically unfavourable water molecule by the inhibitor and improved hydration of the bound ligand. The location of this hydration site was successfully used to enrich virtual screening results in their content of selective Itk inhibitors.