NMR Structure Determination and Rational Drug Design

Abstract

In biological and biomedical research, the area of structural biology, in particular atomic resolution studies of the three-dimensional structure of biological macromolecules and their intermolecular interactions, has never before had as central a role and enjoyed as much popularity as today. This is mainly due to the facts that with the use of DNA recombination and chemical synthesis, a virtually unlimited array of different polypeptide sequences can be generated, and that the relations of the resulting primary structures with corresponding biological functions can only be rationalized through knowledge of the three-dimensional structure. In addition to its key role in academic institutions, structure determination of proteins, nucleic acids and other classes of biomolecules has therefore become a discipline that is actively pursued also in profit-oriented organizations, especially in the major pharmaceutical companies. Although X-ray diffraction with single crystals has for two decades, until 1984, been unique in its potential for efficient determination of three-dimensional molecular structures at atomic resolution, it presently shares this role with nuclear magnetic resonance (NMR) spectroscopy in solution. During the period 1990–1993, 607 new X-ray crystal structures, 179 new NMR solution structures, and 2 structures determined by other methods were published (Hendrickson and Wuthrich, 1991; 1992; 1993; 1994). This article presents a description of the NMR approach for three-dimensional structure determination of biological macromolecules and a discussion of the impact of molecular structural biology in biomedical research.