Identification of chemically diverse, novel inhibitors of 17ß-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening.

17ß-Hydroxysteroid dehydrogenase type 3 and 5 (17ß-HSD3 and 17ß-HSD5) catalyze testosterone biosynthesis and thereby constitute therapeutic targets for androgen-related diseases or endocrine-disrupting chemicals. As a fast and efficient tool to identify potential ligands for 17ßHSD3/5, ligand- and structure-based pharmacophore models for both enzymes were developed. The models were evaluated first by in silico screening of commercial compound databases and further experimentally validated by enzymatic efficacy tests of selected virtual hits. Among the 35 tested compounds, 11 novel inhibitors with distinct chemical scaffolds, e.g. sulfonamides and triazoles, and with different selectivity properties were discovered. Thereby, we provide several potential starting points for further 17ß-HSD3 and 17ß-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors.

Securing reliability and validity in biomedical research: an essential task.

The buzzword 'translational' dominates concepts to optimize value creation from science. This article discusses the impact of 'old' and contemporary data on hypothesis generation in relation to human physiology and in the effort to optimally implement translational sciences. I outline how dogmas and errors, sometimes perpetuated over decades, impact contemporary research and drug discovery projects. As a consequence and to improve value creation from science, a reevaluation of old data (i.e. of the validity and reliability of research with regard to human physiology) seems necessary. In line with this, the compliance of newly generated hypotheses, assays and tools with a conceptual focus on human physiology as the gold standard seems essential. To achieve improved research success, several measures need to be initiated and guided by industrial and academic leaders in concert to have an impact on the quality of research in the very near future. There is no 'holy grail', but in general terms, a constructive but critical approach--not just to contemporary biomedical research--seems mandatory to avoid the errors of the past and enable solutions to evolve dynamically.

The discovery of new 11beta-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening.

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the conversion of biologically inactive 11-ketosteroids into their active 11beta-hydroxy derivatives and vice versa. Inhibition of 11beta-HSD1 has considerable therapeutic potential for glucocorticoid-associated diseases including obesity, diabetes, wound healing, and muscle atrophy. Because inhibition of related enzymes such as 11beta-HSD2 and 17beta-HSDs causes sodium retention and hypertension or interferes with sex steroid hormone metabolism, respectively, highly selective 11beta-HSD1 inhibitors are required for successful therapy. Here, we employed the software package Catalyst to develop ligand-based multifeature pharmacophore models for 11beta-HSD1 inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed several selective inhibitors. Efficient inhibition of recombinant human 11beta-HSD1 in intact transfected cells as well as endogenous enzyme in mouse 3T3-L1 adipocytes and C2C12 myotubes was demonstrated for compound 27, which was able to block subsequent cortisol-dependent activation of glucocorticoid receptors with only minor direct effects on the receptor itself. Our results suggest that inhibitor-based pharmacophore models for 11beta-HSD1 in combination with suitable cell-based activity assays, including such for related enzymes, can be used for the identification of selective and potent inhibitors.