Current Topics in Medicinal Chemistry - Volume 3, Issue 1, 2003

In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and de Read More

There are conceptual differences between high-throughput screening (HTS) and fragment-based screening by NMR. The number of compounds in libraries for NMR screening may be significantly smaller than those used for HTS. Because one relies on a small library its design is significantly important and is the object of this article. A short introduction on fragment-based NMR screening approaches will be provided. Although Read More

The drug discovery process often involves the screening of compound libraries to identify drug candidates capable of binding to target macromolecules. New approaches in biological and chemical research are driving a change in the pharmaceutical industry. Recent advances in NMR spectroscopy such as affinity NMR techniques, which detect binding of a small molecule with a “receptor”, have been shown to be Read More

This article is a review with 83 references of the application of NMR to the measurement of the dissociation constants of protein-ligand complexes. After briefly discussing some general concepts of molecular stability, the text turns to consider which NMR parameters are reporters of complex formation. The available data treatments required to translate observed NMR effects into quantitative measurements of the stability of t Read More

For NMR based screening we review equipment needed for automated preparation of samples and acquisition of a large number of data sets. Hardware connecting lab-bench and NMR spectrometer is described. We focus on software used for automated calculation of the similarity between spectra - a prerequisite for the identification of test compounds interacting with a target-molecule.

One of the prime merits of NMR as a tool for lead finding in drug discovery research is its sensitivity and robustness to detect weak protein-ligand interactions. This sensitivity allows to build up ligands for a given target in a modular way, by a fragmentbased approach. In this approach, two ligands are seperately identified which bind to the target protein generally weakly, but at adjacent binding sites. In a next step, they are Read More

The application of NMR screening in drug discovery has recently attained heightened importance throughout the pharmaceutical industry. NMR screening can be applied at various points in a drug discovery program, ranging from very early in the program, when new targets can be screened long before an HTS enzymatic assay is developed, to later in the program, as in the case where no useful hits have been detec Read More