Discovery of depsides and depsidones from lichen as potent inhibitors of microsomal prostaglandin E2 synthase-1 using pharmacophore models

Abstract

Nature in silico: Virtual screening using validated pharmacophore models identified lichen depsides and depsidones as potential inhibitors of mPGES-1, an emerging target for NSAIDs. Evaluation of the virtual hits in a cell-free assay revealed physodic acid and perlatolic acid as potent inhibitors of mPGES-1 (IC(50) = 0.4 and 0.43 μM, respectively), indicating that these natural products have potential as novel anti-inflammatory agents.

Figure 1

General structures of both the depside and depsidone scaffolds with numbering, and the chemical structures of lichen constituents 1–10 and reference mPGES-1 inhibitor 11.

Figure 2

Inhibition of mPGES-1 by depsides and depsidones from lichen. Concentration–response curves of physodic acid (2), perlatolic acid (8), and olivetoric acid (9) for inhibition of mPGES-1 activity in microsomal preparations of IL-1β-stimulated A549 cells. Experiments were performed as described in the Experimental Section. Data represent the mean ± SE of n=3–4 independent experiments.

Figure 3

Pharmacophore model for acidic mPGES-1 inhibitors. Chemical features are color-coded: hydrophobic (cyan), aromatic ring (gold), negatively ionizable (blue), spatial shape restriction (grey). The screening model M1 required a compound to map all of these features to be considered a virtual hit. During the screening with M2, one hydrophobic feature or the aromatic ring feature was allowed to be omitted. The mPGES-1 inhibitors found in this study (compound 2 in green, 8 in blue, and 9 in grey) all map two of the hydrophobic features with their alkyl chains.