Comparison of a homology model and the crystallographic structure of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a structure-based identification of inhibitors

Abstract

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.

A three-dimensional model of CYP19 aromatase for structure-based drug design

“…The models provide also insights into enzyme catalyzed reaction mechanistic studies. Models that match the experimentally solved structures very closely have also been published [38,39]. Other methods for ligand design include, e.g.…”

Steroid substrate-induced epimerase mechanism in the active site of the human 11&946;-hydroxysteroid dehydrogenase type 1

“…Tyr 183 is located proximal to the bound cofactor within the human 11β-HSD1 active site and is responsible for the reducing activity 18,19 . This is shown in Fig.…”

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

“…Az aktív centrum primer szerkezetében nagy menynyiségű tirozin, lizin és szerin aminosavak vesznek részt (1. ábra C panel). In silico szűrés segítségével a szubsztrátkötő zseb szelektív, természetesen előforduló gátló-szereit azonosították [2].…”

“…A 11-β-HSD-1 enzim háromdimenziós fehérjeszer-kezetének modelljét (1. ábra C panel) felhasználva 15 különböző feltételezett 11-β-HSD-1-inhibitort azonosítottak [2]. A különböző inhibitorok hatásmechaniz-musának vizsgálata során megállapították, hogy a szulfonamidszerkezetű vegyületek a szubsztrát kompetitív inhibitorai, míg a triazolszerkezetű vegyületek nemcsak elfoglalják a katalitikus helyet, hanem módosítják is annak egy részét [2,9].…”

“…A különböző inhibitorok hatásmechaniz-musának vizsgálata során megállapították, hogy a szulfonamidszerkezetű vegyületek a szubsztrát kompetitív inhibitorai, míg a triazolszerkezetű vegyületek nemcsak elfoglalják a katalitikus helyet, hanem módosítják is annak egy részét [2,9].…”