Structural chemoproteomics applied to discovery of GSK inhibitors and PPAR agonists

Abstract

Drug Discovery of durg for an increasingly large number of biological target proteins such as kinases, protein phosphatases and nuclear receptors requires creative and innovative approaches for identifying hit compounds and optimizing those to drug candidates. As a result of enormous technological progress in structural biology and computational chemistry, structure-based drug design has become an essential part in drug discovery and development process. A novel “-omics” concept of structural chemoproteomics is devised for use in drug discovery process. On the basis of structural chemoproteomics, the active sites of proteins from the same family were aligned and analyzed to address the commonalities and differences. The commonalities enabled to make scaffold structures in the structural chemoproteomic library and the differences enable to introduce functional group in the active scaffolds. This thesis describes applying the structural chemoproteomic libraries for kinase inhibitors and for PPAR agonists. A hydroxy functional group was introduced as the hydrogen bond donor and acceptor at the hinge region of protein kinase in order to develop novel ATP-competitive kinase inhibitors. Several derivatives of 7-hydroxyl-1H-benzoimidazole were designed as inhibitors of protein kinase with the help of ab initio calculations and a docking study. Enzymatic assay and an X-ray complex study using glycogen synthase $kinase-3 \beta$ showed that these designed compounds were highly potent ATP-competitive kinase inhibitors. To develop PPAR agonists, the active site was divided into three parts: head, tail and linker. The head part should have hydrogen bond acceptors like carboxylic acid in the lipid ligands, the tail part should be hydrophobic to interact with protein and the linker should make the head and tail parts arrange in an appropriate position. Several sulfamide derivatives were designed with the help of a docking study. Transactivation assay indicates that designe...