Vibrating our way to new drugs. The goal of our research is to determine the transition state structures of enzyme-catalyzed reactions. Using the transition state structure as a guide, we can design new enzyme inhibitors that have the potential to be useful new drugs - e.g. as antibiotics or adjuncts to cancer radiation therapy. By binding the TS, the enzyme stabilizes it and reduces the activation energy for the reaction. If we can capture even a tiny fraction of that binding energy in a stable compound that mimics the TS, we will have a potent inhibitor .
TSs are notoriously difficult to study because of they are unstable.
Ahmed Zewail won the 1999 Nobel Prize in Chemistry for his femtochemistry studies of TSs. By measuring KIEs for many atoms in a substrate molecule, we can determine the structure of the TS with sub- ngstrom resolution. KIEs on atoms close to, but not involved in the chemical reaction, i.e. secondary KIEs, can reveal the structure and conformation of the whole molecule at the TS, not merely the site where bond making and breaking is occurring. Once we have determined the TS structure for an enzymatic reaction, we can start the process of inhibitor design. As we've already seen, enzymes bind the TS, not the substrate or products.