Recent progress in chemical biology research has accelerated the identification of the targets of biologically active small molecules, including naturally occurring protein ligands. A ligand is defined as a molecule that binds to another chemical substance to serve a biological purpose. The goal of this research program is to explore the molecular science underlying the identification of these molecules.
It is widely recognized that a biologically active natural product (or naturally occurring ligand, “NOL”) functions as a small molecular “key” that fits a specific protein “lock”. However, recent studies have revealed that an NOL functions as a “bunch of keys” (or “master key”) that can fit multiple “locks”. Experiments analyzing NOLs have often produced puzzling results, which can likely be attributed to the multi-target nature of NOLs. Thus, the application of any given NOL will depend heavily on the identification of the specific molecular targets involved in the desired activity of that NOL.
The goals of this research project are as follows: 1) to develop a versatile methodology for identifying the target(s) of NOLs; 2) to establish a rational molecular approach to designing a simplified NOL (such as “Halaven”) based on the structure of the ligand/target complex; and 3) to generate new concepts relating to the control of bioactivity that depend on the “master key” characteristics of natural NOLs, for instance, the idea that a living organism selects the precise “master key” bioactivity appropriate for each situation in vivo.
Identification of specific NOL targets (chemical biology) will facilitate the rational molecular design of simplified NOLs (chemistry), and the discovery of new chemical concepts in the control of bioactivity (chemistry). The sequence of our approach is therefore “Chemical Biological → Chemistry”; in other words, a new chemistry arises from achievements in chemical biology.