caa a22 4500 467939004 CHVBK 20180406153006.0 cr unu---uuuuu 170328e20060201xx s 000 0 eng 10.1007/s10822-006-9037-3 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9037-3 Comparison of a homology model and the crystallographic structure of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a structure-based identification of inhibitors [Elektronische Daten] [Laurence Miguet, Ziding Zhang, Maryse Barbier, Martin Grigorov] Summary: Human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of cortisone into active cortisol. 11βHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11βHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11βHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11βHSD1 inhibitors or substrates and non-inhibitors. The homology model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening experiments on both the homology model and the crystallographic structure with a database of 114'000 natural molecules. Among these, 15 molecules were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homology model. Among these putative 11βHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme. Springer Science+Business Media, Inc., 2006 11β-Hydroxysteroid dehydrogenase type 1 nationallicence diabetes type 2 nationallicence homology modeling nationallicence inhibitor nationallicence molecular docking nationallicence Miguet Laurence BioAnalytical Science, Nestlé Research Center, Nestec Ltd, CH-1000, Lausanne 26, Switzerland aut Zhang Ziding Bioinformatics Center, College of Biological Science, China Agricultural University, 100094, Beijing, China aut Barbier Maryse BioAnalytical Science, Nestlé Research Center, Nestec Ltd, CH-1000, Lausanne 26, Switzerland aut Grigorov Martin BioAnalytical Science, Nestlé Research Center, Nestec Ltd, CH-1000, Lausanne 26, Switzerland aut Journal of Computer-Aided Molecular Design Springer Netherlands 20/2(2006-02-01), 67-81 0920-654X 20:2<67 2006 20 10822 https://doi.org/10.1007/s10822-006-9037-3 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9037-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Miguet Laurence BioAnalytical Science, Nestlé Research Center, Nestec Ltd, CH-1000, Lausanne 26, Switzerland aut NATIONALLICENCE 700 1- Zhang Ziding Bioinformatics Center, College of Biological Science, China Agricultural University, 100094, Beijing, China aut NATIONALLICENCE 700 1- Barbier Maryse BioAnalytical Science, Nestlé Research Center, Nestec Ltd, CH-1000, Lausanne 26, Switzerland aut NATIONALLICENCE 700 1- Grigorov Martin BioAnalytical Science, Nestlé Research Center, Nestec Ltd, CH-1000, Lausanne 26, Switzerland aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Springer Netherlands 20/2(2006-02-01), 67-81 0920-654X 20:2<67 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer