New Approaches to NMR Data Acquisition, Assignment and Protein Structure Determination: Potential Impact in Drug Discovery

Abstract

The majority of drugs available today were discovered either from chance observations or from the screening of synthetic or natural product libraries. The chemical modification of lead compounds, on a trial-and-error basis, typically led to compounds with improved potency, selectivity, bioavailability, and reduced toxicity. However, this approach is laborand time-intensive, and researchers in the pharmaceutical industry are constantly developing methods with a view to increasing the efficiency of the drug discovery process. One of these relatively new approaches is the so-called rational drug design that relies heavily in the determination, either by X-ray crystallography or nuclear magnetic resonance (NMR) spesctroscopy, of the three-dimensional structures of the targets and the ligand-target complexes. NMR spectroscopy is a biophysical technique with wide applicability in drug discovery research, particularly for the detection and characterization of molecular interactions. NMR can also be used as a tool for the determination of structure and dynamics of proteins, and protein-ligand complexes. In drug design, NMR can be used to validate or invalidate hits from high-throughputscreening (HTS) and can also generate lead compounds by a fragment-based approach. Thus, NMR is not only a technique for structure-guided drug design, but can also be integrated with HTS and combinatorial chemistry. Being so versatile, NMR can be applied to all phases of a drug discovery program, including target selection, lead generation, and lead optimization [1]. To most pharmaceutical companies structural information is an important contributor to drug discovery programs, and this information is sought and utilized whenever a target appears structurally feasible. For structure determination of large proteins, or the complex of a large protein with a tightly bound inhibitor, structure determination by X-ray crystallography is generally faster. On the contrary, smaller proteins sometimes do not readily crystallize and can be more rapidly solved by NMR. Furthermore, NMR can be applied to the structure determination of weakly bound ligands. The two methods are complementary, and each has its own strengths and weaknesses. From a practical point of view, the main challenges NMR faces in the pharmaceutical world are the costs associated with the production of large amounts of labeled material for screening and structural studies, and, more importantly, the speed with which data are generated. Only when these issues are resolved, will NMR be able to fully exploit its potential in the drug discovery field. This chapter will review some of the methodologies recently developed to increase the efficiency of strategies for data acquisition, analysis, and protein structure calculation by NMR.