Planta Med 2014; 80 - P1L145
DOI: 10.1055/s-0034-1394802

Pistacia lentiscus oleoresin: Virtual screening and in vitro 11β-hydroxysteroid dehydrogenase 1 inhibition

A Assimopoulou 1, A Vuorinen 2, J Seibert 3, V Papageorgiou 1, A Odermatt 3, D Schuster 2, J Rollinger 4
  • 1Department of Chemical Engineering, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
  • 2Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
  • 3Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
  • 4Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria

Pistacia lentiscus var. Chia oleoresin, so called mastic gum, has traditionally been used to treat multiple conditions such as cough, sore throat, eczema, stomach aches, rheumatisms and diabetes [1]. Although clinical trials supporting these uses are limited, an in vivo study previously revealed an antidiabetic activity of P. lentiscus oleoresin [2]. P. lentiscus oleoresin contains a number of penta- and tetra-cyclic triterpenes [1], which exert antidiabetic effects and improve lipid metabolism. We recently identified oleanonic acid as a PPARγ-agonist through bioassay-guided fractionation of mastic gum [3]. Despite these findings, the antidiabetic mechanism of mastic gum remains mainly unknown. In the search for a potential mechanism of action of P. lentiscus oleoresin as traditional antidiabetic medicines, we performed a virtual screening using elaborated and validated pharmacophore models for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition [4]. A small focused database consisting of previously isolated compounds from this plant material was generated and virtually screened. According to the hit list we strongly supposed an interaction of triterpenes from mastic gum with 11β-HSD1, and therefore experimentally investigated the crude oleoresin and its acidic fraction. Additionally the two main constituents and predicted ligands, masticadienonic acid (1) and isomasticadienonic acid (2) (Figure 1), were tested against their inhibitory activity on 11β-HSD1 and 11β-HSD2. The results showed a significant inhibition of both the crude P. lentiscus oleoresin and its acidic fraction as well as a potent and selective inhibition of the two virtual hits 1 and 2 with IC50 s of 2.51 and 1.94µM. These findings suggest that the selective inhibition of 11β-HSD1 may contribute to the antidiabetic activity of mastic gum.

masticadienonic acid (1).

isomasticadienonic acid (2) Fig. 1: Main constituents of the acidic fraction of Pistacia lentiscus oleoresin.

Acknowledgements: A.V. is financed by the DOC program of the Austrian Academy of Sciences (ÖAW).

Keywords: Pistacia lentiscus, mastic gum, 11β-hydroxysteroid dehydrogenase, virtual screening, diabetes, triterpenes, masticadienonic acid, isomasticadienonic acid

References:

[1] Assimopoulou AN, Papageorgiou VP. Oleoresins from Pistacia species: Chemistry and Biology. In: Govil JN, Singh VK, editors. Recent progress in medicinal plants, Natural Products II, vol.18. Studium Press USA; 2007: 146 – 202

[2] Kokolakis AK. Analysis and study of the biological activity of the constituents of the resin from the plant Pistacia lentiscus var. Chia (Chios mastic gum). Master Thesis, Department of Chemistry, University of Crete 2008

[3] Petersen RK, Christensen KB, Assimopoulou AN, Frette X, Papageorgiou VP, Kristiansen K, Kouskoumvekaki I. Pharmacophore-driven identification of novel PPARγ partial agonists from natural sources. J Comput Aided Mol Des 2011; 25: 107 – 116

[4] Schuster D, Maurer EM, Laggner C, Nashev LG, Wilckens T, Langer T, Odermatt T. The discovery of new 11β-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening. J Med Chem 2006; 49: 3454 – 3466