Traditional small molecule drug discovery strategies rely on the “lock and key” theory, which specifies that small molecule drugs bind to target proteins and modulate their functions. However, many disease-related proteins, including substrate binding proteins, aggregation-prone proteins, and protein-protein interactions cannot be predicted by the lock and key mechanism. Therefore, we discovered novel strategies that employ methods of organic chemistry, and molecular and cellular biology to regulate these proteins.
We developed a novel strategy for small molecule drug discovery, in which, degradation of target proteins is based on the use of small hybrid molecules composed of a ligand for the target protein and another for ubiquitin ligase. These hybrid small molecules direct the ubiquitin ligase towards the target protein, leading to selective degradation by the ubiquitin-proteasome system. In addition, we demonstrated that this strategy could be an effective therapeutic approach for neurodegenerative diseases.
Aqueous solubility is essential for drug candidates, and improving aqueous solubility of bioactive compounds is a major concern for medicinal chemists. We have proposed strategies for improving aqueous solubility by modifying molecules using certain methods that would decrease intermolecular interaction. Our results indicate that these strategies can increase the aqueous solubility of molecules although their hydrophobicities increase concomitantly.