Aiming to develop therapeutic agents, medicinal chemistry and chemical biology are conducted in our group. The focused fields of computational molecular design, synthetic reactions, and biological action mechanisms of bio-functional molecules are studied on the basis of organic chemistry.
１．Epigenetic Control Using Synthetic Small Molecules
The term “epigenetics” is defined as “heritable changes in gene expression that occur without changes in DNA sequence”. Recently, it has been revealed that DNA methylation and histone modifications such as acetylation, methylation and phosphorylation are epigenetic mechanisms according to this definition. In other words, these posttranslational modifications are important factors in determining when and where a gene will be expressed.
Compounds that control epigenetics can be utilized as tools for elucidating life phenomena and as therapeutic agents. We are trying to discover specific inhibitors of histone deacetylases and histone demethylases which play pivotal roles in epigenetic gene expression. We are also performing chemical genetics study using those specific inhibitors, which will lead to not only the understanding of the mechanism of diseases that are related to epigenetics but also presenting guideline for therapy.
２．Medicinal Chemistry Using Click Chemistry
Click chemistry is a powerful fragment-based assembly method, and was shown to be highly versatile and effective for rapid synthesis/assembly of libraries of small molecules directed against a number of enzymes. Triazole synthesis by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), a key reaction in click chemistry, can provide a library of triazole-containing compounds which are pure enough to be evaluated by means of in vitro assay without purification. We are trying to find bio-active compounds using click chemistry.
３．Target-guided synthesis of enzyme inhibitors
To date, various target-guided synthesis (TGS) approaches have been developed in which a target protein is actively engaged in the assembly of its own bidentate ligand from a pool of smaller reactive fragments. We are developing new types of TGS to discover drug candidates efficiently.
４．Noncovalent interactions between ligands and proteins
It is well known that reversible ligands bind to target proteins through noncovalent interactions such as hydrogen bonds and hydrophobic interactions. We are examining another manner of noncovalent interaction.