Discovery of 3-hydroxy-3-pyrrolin-2-one-based mPGES-1 inhibitors using a multi-step virtual screening protocol

Abstract

Targeting microsomal prostaglandin E₂ synthase-1 (mPGES-1) represents an efficient strategy for the development of novel drugs against inflammation and cancer with potentially reduced side effects. With this aim, a virtual screening was performed on a large library of commercially available molecules using the X-ray structure of mPGES-1 co-complexed with a potent inhibitor. Combining fast ligand-based shape alignment, molecular docking experiments, and qualitative analysis of the binding poses, a small set of molecules was selected for the subsequent steps of validation of the biological activity. Compounds 2 and 3, bearing the 3-hydroxy-3-pyrrolin-2-one nucleus, showed mPGES-1-inhibitory activity in the low micromolar range. These data highlighted the applicability of the reported virtual screening protocol for the selection of new mPGES-1 inhibitors as promising anti-inflammatory/anti-cancer drugs.

Fig. 1. mPGES-1 structure: A) on the left, transparent molecular surface representation of the mPGES-1 trimer, with chains A, B and C depicted in red, black, and blue ribbons, respectively; on the right, focused representation of the mPGES-1 binding site with transparent molecular surface colored in yellow, orange, and green (see text for details, glutathione (GSH) cofactor and key residues in the mPGES-1 binding site are represented in sticks, C grey, O red, N, blue, polar H white); B) on the left, mPGES-1 co-complexed with LVJ inhibitor (PDB code: 4BPM, LVJ represented in sticks, C cyan, O red, N, blue, polar H white, Cl green, F light green); on the right, two-dimensional panel representing interactions between LVJ and residues in mPGES-1 binding site.

Fig. 2. The virtual screening workflow for the identification of mPGES-1 inhibitors.

Fig. 3. A) Selected 3D pose of 2 (colored by atom types: C, ochre; N, blue; O, red; S, yellow; polar H, light grey; Cl, light green) featuring the highest shape similarity to LVJ, in docking with mPGES-1 (chains A, B and C depicted in red, black, and blue ribbons, transparent molecular surface on the binding site colored in yellow, orange, and green, see text for details, glutathione (GSH) cofactor and key residues in the mPGES-1 binding site are represented in sticks, C grey, O red, N, blue, polar H white); B) related two-dimensional panels representing interactions.

Fig. 4. A) Selected 3D pose of 3 (colored by atom types: C, indigo blue; N, blue; O, red; S, yellow; polar H, light grey; Cl, light green) featuring the highest shape similarity to LVJ, in docking with mPGES-1 (chains A, B and C depicted in red, black, and blue ribbons, transparent molecular surface on the binding site colored in yellow, orange, and green, see text for details, glutathione (GSH) cofactor and key residues in the mPGES-1 binding site are represented in sticks, C grey, O red, N, blue, polar H white); B) related two-dimensional panels representing interactions.