Combinatorial Chemistry & High Throughput Screening - Volume 5, Issue 8, 2002

The SHAPES strategy combines nuclear magnetic resonance (NMR) screening of a library of small drug-like molecules with a variety of complementary methods, such as virtual screening, high throughput enzymatic assays, combinatorial chemistry, X-ray crystallography, and molecular modeling, in a directed search for new medicinal chemistry leads. In the past few years, the SHAPES strategy has found wide Read More

NMR-based screening and virtual, or in silico, screening can be highly complementary and synergistic. NMR-based screening is a rapid and reliable method for validating hits that come from in silico screens. In addition, ligand-binding data derived from NMR-based screens can focus and direct subsequent in silico screening. We will first give a short overview of existing NMR and in silico screening methods, discuss the drawbacks Read More

High-throughput ligand-based NMR screening with competition binding experiments is extended to 19F detection. Fluorine is a favorable nucleus for these experiments because of the significant contribution of the Chemical Shift Anisotropy (CSA) to the 19F transverse relaxation of the ligand signal when bound to a macromolecular target. A low to moderate affinity ligand containing a fluorine atom is used as a reference mole Read More

NMR-based screening has become a powerful method for the identification and analysis of lowmolecular weight organic compounds that bind to protein targets and can be utilized in drug discovery programs. In particular, heteronuclear NMR-based screening can yield information about both the affinity and binding location of potential lead compounds. In addition, heteronuclear NMR-based screening has wide applications in c Read More

NMR based screening has become an important tool in the pharmaceutical industry. Methods that provide information on the location of small molecule binding sites on the surface of a drug target (e. g. SARby- NMR and related techniques) are of particular interest. In order to extend the applicability of such techniques to drug targets of higher molecular weight, selective labeling strategies may be employed. Dualamino a Read More

NMR has proven to be a valuable tool for identifying small molecule drug leads that serve as starting points for lead optimization programs. In addition, NMR screening can also be applied during lead optimization in order to improve the pharmacokinetic properties of a compound. In this paper we review the NMR methods that can be used for this purpose. Several examples are then summarized to demonstrate the useful Read More

Many lead molecules that have high affinity for a therapeutic target in vitro exhibit a reduced efficacy in vivo. Drug binding to human serum albumin is a major contributor to this reduction in potency, and many drug discovery programs expend significant resources preparing compounds that have decreased albumin binding. As rational and structure-based approaches have already been demonstrated to design compoun Read More

Metabonomics is an emerging technology that enables rapid in vivo screening for toxicity, disease state, or drug efficacy. The technology combines the power of high-resolution nuclear magnetic resonance (NMR) techniques with statistical data analysis methods to rapidly evaluate the metabolic “status” of an animal. Complimentary to other profiling technologies like proteomics and genomics, metabonomics provides a fingerprin Read More