KID: A Kinase-Focused Interaction Database and Its Application in the Construction of Kinase-Focused Molecule...

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Protein kinases are crucial drug targets for various diseases.
• Understanding kinase-ligand interactions is key for designing small-molecule kinase inhibitors (SMKIs).
• Existing databases may not fully capture the chemical space relevant to kinase inhibition.

Purpose of the Study:

• To develop a method for extracting kinase-ligand interaction fragments and residues from crystal structures.
• To create a comprehensive kinase-focused interaction database (KID) for SMKI design.
• To generate novel, diverse molecular databases for exploring new SMKIs.

Main Methods:

• Extraction of fragments and amino acid residues from kinase-ligand crystal structures.
• Development of two libraries: hinge-unfocused fragment-amino acid pair library (FAP Lib) and hinge-focused hinge binder library (HB Lib).
• Generation of Recomb_DB and RsdHB_DB databases using fragment recombination and molecular generation methods based on KID.

Main Results:

• Established the kinase-focused interaction database (KID) comprising FAP Lib and HB Lib.
• Generated Recomb_DB (172,346 molecules) and RsdHB_DB (93,030 molecules) with enhanced diversity.
• The generated databases demonstrated superior scaffold and fingerprint diversity compared to existing commercial and non-commercial databases.

Conclusions:

• The kinase-focused interaction database (KID) effectively captures essential kinase-ligand interaction characteristics.
• The generated Recomb_DB and RsdHB_DB databases offer a focused chemical space for novel SMKI exploration.
• KID serves as a valuable resource for advancing the design and discovery of small-molecule kinase inhibitors.