In silico access for the discovery of 11β-HSD1 inhibiting triterpenes from Eriobotrya japonica

Abstract

An elevated activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been associated with metabolic disorders including obesity and type 2 diabetes, with recent findings providing evidence for beneficial effects of 11β-HSD1 inhibitors, making this enzyme a promising therapeutic target [1]. Recently we investigated different extracts of traditionally used anti-diabetic medicinal plants for potential anti-glucocorticoid effects. Among them, the extracts of E. japonica (Thunb.) Lindl. showed a dose-dependent inhibition of 11β-HSD1, with a preferential inhibition of 11β-HSD1 versus 11β-HSD2 measured in cell lysates. These results were confirmed in intact stably transfected HEK-293 cells [2]. In this study the loquat leaves were phytochemically investigated following predictions of a pharmacophore-based virtual screening. Determination of the 11β-HSD1 and 11β-HSD2 inhibitory activities in cell lysates of virtually predicted hits in combination with a bioactivity-guided approach revealed triterpenes from the ursane type as selective, low µmolar inhibitors of 11β-HSD1: corosolic acid (IC50 0.81µM), 3-epicorosolic acid methyl ester (IC50 5.2µM), 2-α hydroxy-3-oxo urs-12-en-28-oic acid (IC50 17µM), tormentic acid methyl ester (IC50 9.4µM), and ursolic acid (IC50 1.9µM). Intriguingly, a mixture of loquat constituents with moderate activities displayed a pronounced additive effect. By means of molecular modeling studies and the identification of the 11β-HSD1 inhibiting 11-keto-ursolic acid (IC50 2.1µM) and 3-acetyl-11-keto-ursolic acid (IC50 1.3µM) a structure-activity relationship was deduced for this group of pentacyclic triterpenes [3]. The mechanism elucidated in this study together with previously determined pharmacological activities provides this class of compounds from loquat with an astonishing multi-targeted anti-diabetic profile.