KLIFS: A knowledge-based structural database to navigate kinase-ligand interaction space

TY - JOUR

T1 - KLIFS

T2 - A knowledge-based structural database to navigate kinase-ligand interaction space

AU - Van Linden, Oscar P.J.

AU - Kooistra, Albert J.

AU - Leurs, Rob

AU - De Esch, Iwan J.P.

AU - De Graaf, Chris

PY - 2014/1/23

Y1 - 2014/1/23

N2 - Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.

AB - Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies.

UR - http://www.scopus.com/inward/record.url?scp=84893065058&partnerID=8YFLogxK

U2 - 10.1021/jm400378w

DO - 10.1021/jm400378w

M3 - Review

C2 - 23941661

AN - SCOPUS:84893065058

SN - 0022-2623

VL - 57

SP - 249

EP - 277

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -