Stilbene analogs are a new class of anti-inflammatory compounds that effectively inhibit COX-2, which is the major target in the treatment of inflammation and pain. In this study, docking simulations were conducted using AutoDock 4 software that focused on the binding of this class of compounds to COX-2 protein. Our aim was to better understand the structural and chemical features responsible for the recognition mechanism of these compounds, and to explore their binding modes of interaction at the active site by comparing them with COX-2 co-crystallized with SC-558. The docking results allowed us to provide a plausible explanation for the different binding affinities observed experimentally. These results show that important conserved residues, in particular Arg513, Phe518, Trp387, Leu352, Leu531 and Arg120, could be essential for the binding of the ligands to COX-2 protein. The quality of the docking model was estimated based on the binding energies of the studied compounds. A good correlation was obtained between experimental logAr values and the predicted binding energies of the studied compounds.

Pyridopyrimidine-based analogues are among the most highly potent and selective antagonists of cholecystokinin receptor subtype-1 (CCK1R) described to date. To better understand the structural and chemical features responsible for the recognition mechanism, and to explore the binding pocket of these compounds, we performed automated molecular docking using GOLD2.2 software on some derivatives with structural diversity, and propose a putative binding conformation for each compound. The docking protocol was guided by the key role of the Asn333 residue, as revealed by site directed mutagenesis studies. The results suggest two putative binding modes located in the same pocket. Both are characterized by interaction with the main residues revealed by experiment, Asn333 and Arg336, and differ in the spatial position of the Boc-Trp moiety of these compounds. Hydrophobic contacts with residues Thr117, Phe107, Ile352 and Ile329 are also in agreement with experimental data. Despite the poor correlation obtained between the estimated binding energies and the experimental activity, the proposed models allow us to suggest a plausible explanation of the observed binding data in accordance with chemical characteristics of the compounds, and also to explain the observed diastereoselectivity of this family of antagonists towards CCK1R. The most reasonable selected binding conformations could be the starting point for future studies. Figure Superimposition of the two putative binding conformations revealed by molecular docking for pyridopyrimidine-based CCK1 antagonists.