Showing papers by "Beat Ernst published in 2005"

Drug Discovery Today

Abstract: 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 development process has gained marked enhancement in speed and efficiency. In parallel to this development, major pharma companies are increasingly outsourcing many components of drug discovery research to biotech companies. All these measures are designed to address the need for a faster time to market. New screening methodologies have contributed significantly to the efficiency of the drug discovery process. The conventional screening of single compounds or compound libraries has been dramatically accelerated by high throughput screening methods. In addition, in silico screening methods allow the evaluation of virtual compounds. A wide range of new lead finding and lead optimization opportunities result from novel screening methods by NMR, which are the topic of this review article.

Impact of induced fit on ligand binding to the androgen receptor: a multidimensional QSAR study to predict endocrine-disrupting effects of environmental chemicals.

Abstract: We investigated the influence of induced fit of the androgen receptor binding pocket on free energies of ligand binding. On the basis of a novel alignment procedure using flexible docking, molecular dynamics simulations, and linear-interaction energy analysis, we simulated the binding of 119 molecules representing six compound classes. The superposition of the ligand molecules emerging from the combined protocol served as input for Raptor, a receptor-modeling tool based on multidimensional QSAR allowing for ligand-dependent induced fit. Throughout our study, protein flexibility was explicitly accounted for. The model converged at a cross-validated r2 = 0.858 (88 training compounds) and yielded a predictive r2 = 0.792 (26 test compounds), thereby predicting the binding affinity of all compounds close to their experimental value. We then challenged the model by testing five molecules not belonging to compound classes used to train the model: the IC50 values were predicted within a factor of 4.5 compared to...

Molecular cloning and functional expression of a novel Helicobacter pylori α-1,4 fucosyltransferase

Abstract: Helicobacter pylori is an important human pathogen which causes both gastric and duodenal ulcers and is associated with gastric cancer and lymphoma. This microorganism synthesizes fucosylated oligosaccharides, predominantly the Galb-1,4GlcNAc (Type II) blood group antigens Lewis X and Y, whereas a small population also expresses the Galb-1,3GlcNAc (Type I) blood group antigens Lewis A and B. These carbohydrate structures are known to mimic host cell antigens and permit the bacteria to escape from the host immune response. Here, we report the cloning and characterization of a novel H. pylori [alpha]-1,4 fucosyltransferase (FucT). In contrast to the family members characterized to date, this enzyme shows exclusively Type I acceptor substrate specificity. The enzyme consisting of 432 amino acids (MW 50,502 Da) was cloned using a polymerase chain reaction (PCR)-based approach. It exhibits a high degree of identity (75-87%) and similar structural features, for example, in the heptamer repeat pattern, with other H. pylori FucTs. The kinetic characterization revealed a very efficient transferase (k[subscript cat]/K[subscript m] = 229 mM²¹s²¹) for the Type I acceptor substrate (Gal)-1,3 GlcNAc-Lem (1). Additionally, the enzyme possesses a broad tolerance toward nonnatural Type I acceptor substrate analogs and therefore represents a valuable tool for the chemoenzymatic synthesis of Lewis A, sialyl Lewis A as well as mimetics thereof.