Structure- and Dynamics-guided Drug Development Using NMR and its Application to Diverse Pharmaceutical Modalities

Abstract

Nuclear magnetic resonance (NMR) has the unique strength to provide quantitative dynamics information of the systems of interest at atomic resolution under various physiological conditions. Taking advantage of these unique characteristics, solution-state NMR spectroscopy has unveiled the functional dynamics of biological systems and now opens a new avenue to advanced structure-guided drug development that actively utilizes conformational dynamics information. Conformational dynamics revealed by NMR have been utilized to develop better ligands with preferable thermodynamics and kinetics. In addition, the characteristics of conformational dynamics information from NMR are suitable to promote the development of new pharmaceutical modalities, such as biomedicines and medium-size molecules. These new modalities are intrinsically more flexible than small molecule ligands and thus require non-destructive measurements under physiological conditions. Toward this end, we overview recent developments in NMR strategies and the applications of the NMR techniques for higher-ordered structure analysis of biopharmaceuticals, improvement of protein druggability, and understanding the cell permeabilization activity of medium-size molecules. We also discuss a future perspective toward in vivo structure-guided drug development based on the structure and dynamics analysis using in-cell NMR techniques.