ProfKin: A Comprehensive Web Server for Structure-based Kinase Selectivity Profiling

Abstract

Protein kinases are central mediators of signal-transduction cascades and attractive drug targets for therapeutic intervention. Since kinases are structurally and mechanistically related to each other, kinase inhibitor selectivity is often investigated by kinase profiling and considered as an important index for drug discovery. We here describe a versatile web server termed ProfKin for structure-based kinase selectivity profiling, which is based on a kinase-ligand focused database (KinLigDB). It provides all ready-to-use 3D structure coordinates of 4,219 kinase-ligand complex structures covering 297 human kinases and the associated information, particularly including binding site type, binding ligand type, interaction fingerprints, downstream molecules and related human diseases. The web server works via predicting possible binding modes for the query molecule, prioritizing the binding modes guided by an interaction fingerprint analysis method, and giving a list of ranked kinases by a comprehensive index. Users can freely select entire or part of the KinLigDB database, e.g. via subfamily and binding site type, to customize the profiling contents. The superimpositions of the predicted binding poses of the query molecule with reference binding modes can be visually inspected on the website. For each top-ranked kinase, the additional classification attributes and the phylogenetic tree are given simultaneously.

Structure- and Similarity-Based Survey of Allosteric Kinase Inhibitors, Activators, and Closely Related Compounds

“…X-ray structures of complexes between allosteric ligands and human kinases (excluding atypical kinases) and associated data were extracted from the PDB, KLIFS, Profkin, and ASD databases. For X-ray structures, PDB codes were collected and UniProt IDs of kinases identified.…”

An overview of kinase downregulators and recent advances in discovery approaches

“…Based on a KinLigDB (kinase-ligand-focused database), ProfKin, which provides the complex structures of 4219 kinase ligands covering 297 human kinases, associated information, binding site type, ligand binding type, interaction fingerprints, downstream signal pathways, and related human diseases, has been exploited as a multifunctional website for structure-based kinase selectivity profiling. 193 The website ( http://www.lilab-ecust.cn/profkin/ ) can be used to predict the possible binding modes, which can be helpful for target prediction and mechanistic study.…”