Computational Prioritization of Novel Nabumetone-Derived Heterocycles as Potential Cyclooxygenase-2 Inhibitors

Abstract

Purpose: To prioritize fifteen novel nabumetone-derived heterocycles as potential cyclooxygenase-2 inhibitors using an integrated in silico workflow. Methods: Compounds N1-N15 were evaluated by molecular docking against meloxicam-bound murine cyclooxygenase-2 (PDB ID: 4M11) using MOE 2019. The protocol was validated by meloxicam re-docking. The highest-ranked compound, N9, was further examined using a 100-ns GROMACS molecular dynamics trajectory. SwissADME and ADMETlab 3.0 were used for drug-likeness, pharmacokinetic and toxicity prediction. Results: Meloxicam scored -7.256 kcal/mol, whereas all designed compounds produced more negative docking scores. N9 ranked first (-9.636 kcal/mol), followed by N14 and N13. Its predicted pose involved Tyr355 and Val116 hydrogen bonds with additional hydrophobic contacts. During the molecular dynamics trajectory, protein and ligand motion became bounded after the initial relaxation period, while compactness and persistent contacts were maintained. N9 showed high predicted gastrointestinal absorption, no blood-brain barrier permeation and no Lipinski violations. However, toxicity prediction indicated potential safety liabilities, including drug-induced liver injury, genotoxicity and neurotoxicity. Conclusions: N9 is the top candidate in this computational series and should be synthesized and tested for cyclooxygenase inhibition, anti-inflammatory activity and safety.