Discovery of selective mPGES-1 inhibitors through pharmacophore modeling, molecular docking, and quantum chemical analysis.

The overexpression of microsomal prostaglandin E2 synthase-1 (mPGES-1), a terminal enzyme in the COX/mPGES-1/PGE2 pathway, has been strongly implicated in cancer progression through its role in inflammation, immune evasion, and tumour proliferation. In this study, we employed a comprehensive ligand-based drug design strategy to identify novel, selective mPGES-1 inhibitors with potential anticancer activity. A pharmacophore model was generated using high-affinity ligands (IC50 < 50 nM) and validated with DUD-E decoy datasets, achieving a sensitivity of 0.88 and specificity of 0.95. Virtual screening of the ZINC database yielded 19,334 hits, which were filtered using Lipinski's Rule of Five and prioritized through docking studies with the 4BPM crystal structure of mPGES-1. Among the top candidates, Compound 39 (ZINC58293998) has a molecular formula of C19H17N5OS, and its structural formula is represented by the SMILES notation: OC1C([H]) = C(NC(N([H])/NC(C([H])([H])[H])\C2C(C([H]) = C3C(N([H])C4C([H])C([H]) = C(C([H]) = C4S3)[H]) = C2[H])[H])N1[H])C([H])([H])[H], providing insight into its chemical structure and potential interaction capabilities which demonstrated the most favorable docking score (-8.08 kcal/mol) and consistent binding interactions, including key residues Arg67 and Arg70. ADME profiling revealed high gastrointestinal absorption and low toxicity, while in silico toxicity models confirmed a lack of hepatotoxicity, mutagenicity, and immunotoxicity. Molecular dynamics simulations (100 ns) confirmed the structural stability of the Compound 39-mPGES-1 complex, with low RMSD fluctuations and strong protein-ligand contacts. Density functional theory (DFT) calculations indicated high chemical reactivity and electron-donating potential, further supporting its bioactive profile. MM-GBSA binding free energy (-35.70 kcal/mol) and principal component analysis placed Compound 39 within the physicochemical space of FDA-approved drugs. Collectively, our integrated in silico pipeline highlights Compound 39 as a promising lead for selective mPGES-1 inhibition and warrants further preclinical investigation as a potential anti-cancer therapeutic.