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

Protein kinases are important drug targets for the treatment
of
several diseases. The interaction between kinases and ligands is vital
in the process of small-molecule kinase inhibitor (SMKI) design. In
this study, we propose a method to extract fragments and amino acid
residues from crystal structures for kinase–ligand interactions.
In addition, core fragments that interact with the important hinge
region of kinases were extracted along with their decorations. Based
on the superimposed structural data of kinases from the kinase–ligand
interaction fingerprint and structure database, we obtained two libraries,
namely, a hinge-unfocused fragment–amino acid pair library
(FAP Lib) that contains 6672 pairs of fragments and corresponding
amino-acids, and a hinge-focused hinge binder library (HB Lib) of
3560 pairs of hinge-binding scaffolds with their corresponding decorations.
These two libraries constitute a kinase-focused interaction database
(KID). In depth analysis was conducted on KID to explore important
characteristics of fragments in the design of SMKIs. With KID, we
built two kinase-focused molecule databases, one called Recomb_DB,
which contains 1,72,346 molecules generated through fragment recombination
based on the FAP Lib, and another called RsdHB_DB, which contains
93,030 molecules generated based on our HB Lib using molecular generation
methods. Compared with five databases both commercial and non-commercial,
these two databases both ranked top 3 in scaffold diversity, top 4
in molecule fingerprint diversity, and are more focused on the chemical
space of kinase inhibitors. Hence, KID presents a useful addition
to existing databases for the exploration of novel SMKIs.