Cao_2026_Chem.Biol.Interact__112149

Organophosphate esters (OPEs) are widespread environmental contaminants increasingly recognized for their metabolic-disruption potential. However, systematic cross-structure comparisons of their inhibitory effects on human carboxylesterase 1 (hCES1), an enzyme involved in xenobiotic metabolism and lipid homeostasis, remain limited. Here, we established an OPE-centered cross-structure inhibition dataset for hCES1 using 25 structurally diverse organophosphate compounds, revealing a pronounced structure-dependent potency pattern across the series (IC(50): 2.538 nM to > 600 microM). More potent inhibition was enriched among compounds bearing P=O motifs and aryl-containing substituents, although the overall activity pattern could not be explained by any single empirical structural label. To resolve the determinants underlying this stratification, we developed complementary QSAR models. The 2D-QSAR models captured global descriptor-level trends but showed only moderate predictive ability (R(2) <= 0.918, q(2) <= 0.508), whereas the scaffold-based 3D-QSAR models (CoMFA and CoMSIA) offered a more spatially informative explanation of activity variation (R(2) <= 0.947, q(2) <= 0.374, RMSE >= 0.420), indicating that steric, electrostatic, hydrophobic, and hydrogen-bonding effects jointly shape hCES1 inhibition. Molecular docking further showed that more potent aryl-rich compounds achieved broader hydrophobic occupancy and denser nonpolar contacts within the hCES1 catalytic cavity. Complementary quantum-chemical analyses indicated that the phosphorus center was the major electron-deficient site, while phosphorus-centered bonding environments and side-chain features contributed differently to electrophilic susceptibility and pocket recognition. Overall, hCES1 inhibition by organophosphate compounds can be interpreted within a layered SAR framework in which side-chain-mediated cavity recognition and phosphorus-centered electronic effects jointly shape inhibitory activity.