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Profile Introduction The concept of structure-based drug design (SBDD) requires detailed knowledge of the three-dimensional (3-D) structure of biological macromolecules, particularly proteins. SBDC relies on the determination of the 3-D structure of an "active part" of a particular biological molecule that is suspected of being involved in the etiology of a disease. The drug discovery process ranges from the simple identification of whether a compound binds to a given protein to the determination of the full three-dimensional structure of the complex. The biological molecule may e.g. be a receptor, an enzyme, a hormone, or any other biologically or immunologically active molecule. Once the 3-D structure of biological molecule, or at least its active site, is known, scientists can use computer modeling to design molecules that will block, mimic or enhance the natural biological activity of the molecule. Knowledge of the 3-D structure of biological molecules at high resolution is therefore of great medical and commercial significance. Available methods (X-ray crystallography and NMR-spectroscopy) require milligram amounts of highly purified proteins. The use of X-ray diffraction is limited to molecules that can be crystallized. Unfortunately only a small minority of membrane proteins have so far produced suitable crystals. Nuclear magnetic resonance ("NMR") spectroscopy, discovered by Felix Bloch and Edward Purcell in 1946, is amenable to in principle any biomolecule of interest, including transmembrane proteins and other molecules that are refractory to crystallization. Today such strategies as SAR by NMR (structure-activity relationship by nuclear magnetic resonance) "shapes screening" and "NMR-Solve" already have wide application in drug discovery. Solid State NMR (SS NMR) is the only technique that has the potential of becoming a versatile tool for membrane protein structure determination, including in situ ligand structure. These proteins are essential parts of biological membranes and confer diverse functions, such as energy conservation, molecular transport, signal transduction or cell recognition and biosynthesis of lipids. The enormous economical potential of membrane proteins is high-lighted by the family of G-protein-coupled coupled receptors, against which approx. 60% of all prescription drugs are targeted.Solid state NMR allows direct examination of a membrane protein in a native environment either as a single species (reconstituted in defined lipids) or in a heterogeneous environment with other proteins and lipids (natural membranes). Stable isotopes
for NMR
Only a few NMR active nuclei occur at high natural abundance (31P, 19F). Most nuclei are NMR inactive. The most commonly used stable isotopes for macromolecular NMR are 13C, 15N, and 2H. For larger molecules, such as proteins, a sufficiently strong signal in NMR spectra requires enrichment with NMR active stable isotopes. Uniform isotope labeling, selective labeling and segmental labeling are known labeling techniques that are applied in the NMR. Uniform isotope labeling in principle allows de novo determination of protein structure. Selective labeling of individual amino acids or certain amino-acid types in proteins may be required to simplify the spectrum and help in assignment. A variant approach is "segmental labeling" in which discrete segments of the polypeptide chain are uniformly labeled 
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