earticle

영어

Drug molecules usually bind to target proteins controlling their functions to exert pharmacological
effects. The binding between a drug molecule and a protein is initiated by mutual recognition of their three-dimensional (3D) structures which implicate physicochemical properties. Thus, exploring the structural aspects of the recognition is important for understanding drug action mechanisms. Moreover, it enables us to discover new chemicals that fit the active site and mediate the function of the target protein. Such chemicals become drug candidates if they demonstrate proper pharmacokinetics and pharmacological effects without significant toxicity events. Studies for the recognition consist of determination and analysis of the 3D structures of target proteins with bound ligands, more importantly drug molecules. In detail, most 3D structures of iso-type proteins in a family, if not all, have been collected and/or determined for structural analysis. Complex structures have been compared to identify main structural features such as non-bonding interactions, pocket structures, and conformational changes between the proteins and the chemicals in their binding sites. The purpose of this study is conceptually different from that of the “structural proteomics” although we use the same research tools as it does. The structural proteomics generally identifies molecular functions of proteins through the determination of entire protein structures and the comparison of their functional domains. On the other hand, our approach takes advantage of the 3D aspects of the recognition between proteins and ligands, and applies them to drug discovery, being, therefore, named “structural chemoproteomics”. During last several years, CrystalGenomics has applied this method for
the discovery of various drug candidates. Specifically we focused on proteins in the epigenetics and signal transductions. They include families of histone deactylases (HDACs), histone methyl
transferases (HMTs) and kinases. In this presentation, we would like to introduce the ethodology of structural chemoproteomics based drug discovery and discuss recent results obtained from their applications for the discovery of molecular targeted anticancer drug candidates.