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

Abstract

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.