KLIFS

KLIFS provides a curated structural database of kinase–ligand complexes enabling systematic analysis of human and mouse kinase structures from the Protein Data Bank (PDB) to support structure-based investigation of kinase–inhibitor interactions and drug design.

Key Features:

• Kinase coverage: Integration of approved drugs and inhibitors in clinical trials and extension of coverage to atypical kinases alongside eukaryotic protein kinases (ePKs), noting structural differences such as altered hydrophobic spines.
• Structural dataset: Analysis based on over 2,900 human and mouse kinase structures derived from the Protein Data Bank (PDB).
• Binding site alignment: Consistent alignment of 85 kinase ligand binding site residues across structures.
• Systematic interaction analysis: Systematic analysis of kinase–ligand interactions across all regions of the catalytic cleft to identify family-specific interaction features.
• Ligand classification: Classification of ligands according to their binding modes.
• Molecular interaction fingerprints (IFP): Generation and use of molecular interaction fingerprint analysis to characterize interactions.
• Automated annotation: Automated annotation methods to assess ligand-targeted subpockets and analyze DFG and αC-helix conformations.
• Sequence/structure protocols: Protocols for generating sequence/structure alignments and curating ligand atom and bond typing for accurate analyses.
• Hot spot and scaffold analysis: Identification of conserved and selective kinase interaction hot spots and their accommodation of diverse chemical scaffolds.

Scientific Applications:

• Structure-based drug design: Support design and optimization of kinase inhibitors, including analysis of approved drugs and clinical-trial inhibitors.
• Interaction mapping: Map family-specific and conserved interaction hot spots across the catalytic cleft.
• Binding mode analysis: Inform selectivity and scaffold design by classifying ligand binding modes.
• Conformational analysis: Analyze DFG and αC-helix conformations relevant to inhibitor binding states.
• Comparative kinase studies: Compare eukaryotic protein kinases (ePKs) and atypical kinases to reveal structural differences affecting ligand binding.

Methodology:

Computational methods include consistent alignment of 85 ligand binding site residues, systematic analysis of kinase–ligand interactions across the catalytic cleft, automated annotation to assess ligand-targeted subpockets and DFG/αC-helix conformations, protocols for sequence/structure alignments and ligand atom/bond typing, and molecular interaction fingerprint (IFP) analysis.