Discovery of novel microsomal prostaglandin E₂ synthase 1 (mPGES-1) inhibitors by a structurally inspired virtual...

Prostaglandin (PG) E₂ is a pro-inflammatory lipid mediator derived from the metabolism of arachidonic acid (AA) by cyclooxygenases (COX) and PGE₂ synthases. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used in the treatment of inflammation, nonselectively inhibit COX activity and decrease PGE₂ production. However, these drugs cause gastrointestinal bleeding and several cardiovascular complications. Therefore, inhibiting microsomal PGE₂ Synthase-1 (mPGES-1) to block PGE₂ production downstream of COX is expected to yield safer and more effective treatments for inflammation, cancer, and cardiovascular diseases. At present, there are no mPGES-1 inhibitors available on the market, but ongoing research continuously evaluates new compounds in both preclinical and clinical stages. Here, we conducted a high throughput virtual screening campaign to discover novel mPGES-1 inhibitor scaffolds. This campaign utilized physicochemical filtering alongside both structure-aware ligand-based approaches (shape screening templates and pharmacophore models, which were generated based on the 3D binding modes of the co-crystallized mPGES-1 inhibitors) and structure-based strategies (refinement with docking and molecular dynamics). Thirty-four compounds were selected and biologically tested for mPGES-1 inhibition in a cell-free assay using microsomes from interleukin-1β-stimulated A549 cells as the source of mPGES-1. The most potent compound inhibited the remaining enzyme activity with an IC₅₀ value of 6.46 μM in a cell-free assay for PGE₂ production. We also compared the binding patterns of the most active compounds identified in this study with those of co-crystallized inhibitors using molecular dynamics simulations. This comparison underscored the crucial role of ionic interactions, π-π interactions, hydrogen bonds, and water bridges involving specific amino acids. Our results highlight the importance of these interaction networks within the binding cavity in various binding scenarios. Ultimately, the insights gained from this study could assist in designing and developing new mPGES-1 inhibitors.