Abstract
<jats:p>Non-steroidal anti-inflammatory drugs represent one of the most widely used classes of therapeutic agents globally [1]. While traditional non-selective drugs inhibit both cyclooxygenase-1 and cyclooxygenase-2, second-generation selective cyclooxygenase-2 inhibitors were rationally designed to minimize gastrointestinal toxicity [2]. However, the secondary effects of these structural changes on pharmacokinetic profiles and tissue distribution are not fully explored. In this study, an integrated computational workflow combining ADME profiling and molecular docking simulations was applied across eight representative drugs divided into five non-selective agents and three selective cyclooxygenase-2 inhibitors. Molecular docking into crystal structures of cyclooxygenase-1 (PDB ID: 1EQG) and cyclooxygenase-2 (PDB ID: 6COX) confirmed that selective inhibitors bind with significantly stronger affinity to cyclooxygenase-2 compared to non-selective agents (p = 0.023), resulting in a pronounced selectivity differential (p = 0.004) [3, 4]. Inferential statistical testing revealed that targeting the secondary active-site pocket of cyclooxygenase-2 requires bulky, polar extension groups that significantly increase molecular weight (p = 0.012) and topological polar surface area (p = 0.041) [5]. Consequently, while all evaluated compounds retained high gastrointestinal absorption and complete Lipinski rule compliance, every selective inhibitor was excluded from crossing the blood-brain barrier [5, 6]. These findings highlight a fundamental biophysical trade-off in drug design, showing that engineering structural selectivity for peripheral gastroprotection inherently limits central nervous system penetration.</jats:p>