Pharmacophore as Fundamental Base of the NSAIDs Design: Molecular Docking and SAR/QSAR Analysis of Reported Experimental Data of Cyclooxygenase 1 and 2

Through comprehensive QSAR analyses and molecular docking studies on COX-1 and COX-2, we successfully identified the pharmacophoric structure and essential moieties that account for the recognition of non-selective COX NSAIDs, such as aro-matic-carboxylate moiety anchors and guides the binding with the guanidinium group of arginine residue, in contrast, the accessory moieties modulate the affinity and blocking of the oxidation of substrate via free radicals. Therefore, the carboxylate group and the aromatic ring are not only important for docking and recognition by COXs, but the cap-todative effect between the carboxylate and the electron-donating group at position 2 is relevant for the stabilization of free radicals, mainly in salicylates and fenamates. Finally, the medical significance of these drugs is substantial and diverse, affecting various acute and chronic inflammatory and pain conditions, with their activity primarily depending on COX-1 and COX-2 inhibition. This research established the physicochemical, molec-ular, and intermolecular interaction basis of non-selective NSAIDs that determine their recognition by these enzymes, thereby providing a molecular foundation for the design of COX inhibitor drugs.