Computational exploration of N-Aryl-3-acylindole derivatives targeting COX-2 and the thromboxane A₂ receptor

Selective inhibition of cyclooxygenase-2 (COX-2) reduces inflammatory prostaglandin production but is associated with cardiovascular risk due to an imbalance between prostacyclin and thromboxane A₂ signalling. This study explores a dual-target strategy using a series of rationally designed N-aryl-3-acylindole derivatives evaluated through an integrated in silico workflow. Molecular docking identified five compounds with favourable binding affinities (≤ −9.0 kcal/mol) toward both Cyclooxygenase-2 and the thromboxane A₂ (TP) receptor. Molecular dynamics simulations (50 ns for COX-2 and 100 ns for TP receptor) indicated stable ligand accommodation without significant structural perturbation. Molecular Mechanics/Generalised Born Surface Area (MM-GBSA) calculations were applied to COX-2 complexes and indicated favourable relative binding free energies predominantly driven by van der Waals and electrostatic contributions. In silico Absorption, Distribution, Metabolism, and Excretion (ADME) profiling suggested acceptable physicochemical properties across the series. Overall, the results indicate that the N-aryl-3-acylindole scaffold is computationally compatible with both targets, supporting its potential as a basis for further optimisation and experimental validation.