J Comput Aided Mol Des 2006 Feb 20;20(2):67-81. Epub 2006 Apr 20.
BioAnalytical Science, Nestlé Research Center, Nestec Ltd, CH-1000, Lausanne 26, Switzerland.
Human 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) catalyzes the interconversion of cortisone into active cortisol. 11betaHSD1 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 11betaHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11betaHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11betaHSD1 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 11betaHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme.