Discovery and Functional Validation of EP3 Receptor Ligands with Therapeutic Potential in Cardiovascular Disease

The prostaglandin E2 receptor EP3 is emerging as a promising therapeutic target in cardiovascular disease due to its involvement in vascular inflammation, platelet aggregation, and vasoconstriction. However, selective EP3 ligands with validated biological activity remain scarce. Here, we combine computational and experimental strategies to discover and validate novel EP3 receptor ligands with therapeutic potential. We implemented a high-throughput, structure- and ligand- based virtual screening pipeline, enabling the efficient exploration of approved drugs and natural compounds from DrugBank and FooDB libraries. Top-scoring candidates were prioritized based on binding energy, and pharmacophoric similarity. Selected hits underwent in silico ADME/Tox profiling using QikProp, identifying molecules with favorable pharmacokinetic and safety parameters. TUCA, masoprocol, and pravastatin sodium emerged as lead candidates and were validated in vitro using endothelial migration and platelet aggregation assays. TUCA exhibited the most consistent inhibitory effect on endothelial migration, while masoprocol, and hydrocortisone significantly reduced platelet aggregation. These findings establish a multidimensional workflow for the rational identification of EP3 ligands and support their potential in cardiovascular therapeutics.