Endometrial cancer is one of the most common gynecological cancers, with new global cases of approximately 420,000 new cases and 98,000 global deaths annually. Emerging evidence suggests that the EP2 receptor plays a critical role in tumor progression, angiogenesis, and immune evasion. Withanolides, a class of naturally occurring compounds, possess anticancer activity; however, the effect of the EP2 receptor in endometrial cancer remains largely unexplored. This study aims to explore the interaction between withanolides and the EP2 receptor using molecular docking techniques, with PF-04418948 as the reference antagonist. A select number of these ligands, with anticancer activity, were evaluated for their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and those with favorable drug-like properties, low toxicity profile, and no more than one Lipinski’s rule violation were docked to EP2 (PDB ID: 7CX2). Molecular docking studies revealed three ligands, (Pubchem 161671, 265237, and 21679027) with significantly higher binding affinity scores compared to that of the reference compound. Pubchem 161671 showed the highest binding affinity at −12.6 kcal/mol. Post-dock analysis revealed interactions with key amino acids, VAL89, LEU298, SER305, and MET31, which are essential for the antagonist activity of the EP2 receptor enzyme. Significant interaction with critical amino acid residues suggested potential inhibition of EP2 receptor activity, offering a potential therapeutic approach for treating endometrial cancer. Overall, this study proffers a deeper understanding of the potential of withanolides as leads for EP2 targeted therapy in endometrial cancer.
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