Structural dynamic approach as rational input for drug design

Conformational flexibility and molecular dynamics play an important role in protein function. Quantification and structural characterization of protein flexibility is essential for the assignment of both the physiological and molecular mechanisms of biological macromolecules. Structural and spectroscopic tools have emerged that allow the study of local and global changes in protein structure and dynamics involved in ligand binding, protein activation, and protein-protein interactions. We have recently introduced the use of time-resolved freeze-quench X-ray absorption spectroscopy (XAS) to study detailed reaction mechanisms of metalloenzymes. Combining such measurements with molecular dynamics simulations provides novel insights into the reaction mechanism. Here we discuss the utilization of this structural dynamic approach to the design of novel inhibitors.