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

Xiaowen Dai, Yuan Xu, Haodi Qiu, Xu Qian, Mingde Lin, Lin Luo, Yang Zhao, Dingfang Huang, Yanmin Zhang, Yadong Chen, Haichun Liu, Yulei Jiang

Journal of chemical information and modeling 2022 Dec 12

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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.

Citation

Xiaowen Dai, Yuan Xu, Haodi Qiu, Xu Qian, Mingde Lin, Lin Luo, Yang Zhao, Dingfang Huang, Yanmin Zhang, Yadong Chen, Haichun Liu, Yulei Jiang. KID: A Kinase-Focused Interaction Database and Its Application in the Construction of Kinase-Focused Molecule Databases. Journal of chemical information and modeling. 2022 Dec 12;62(23):6022-6034