Planta Med 2010; 76 - SL_14
DOI: 10.1055/s-0030-1264252

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

J Rollinger 1, D Kratschmar 2, D Schuster 1, P Pfisterer 1, S Brandstötter 1, H Stuppner 1, G Wolber 1, A Odermatt 2
  • 1University of Innsbruck, Institute of Pharmacy/Pharmacognosy, Innrain 52c, 6020 Innsbruck, Austria
  • 2University of Basel, Department of Pharmaceutical Sciences, Klingelbergstr. 50, 4056 Basel, Switzerland

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.

Acknowledgements: This work was granted by the Austrian Federal Ministry of Science and Research and the Austrian Federal Ministry of Health within the Project „Treatment of Metabolic Syndrome by Traditional Chinese Medicine“, and the Swiss National Science Foundation, N°31003A-124912.

References: 1. Odermatt A; Nashev LG (2010)J Steroid Biochem Mol Biol 119: 1–13.

2. Gumy C; et al. (2009) Fitoterapia 80: 200–5.

3. Rollinger JM; et al. (2010) Bioorg Med Chem 18: 1507–15.