Identification of Diosmetin, Arbutin, and Phenyl Glucoside as Novel Inhibitors from Origanum majorana Targeting Human Cyclooxygenase-2 Enzyme: Insight from Virtual Screening, MD Simulation and Density Functional Theory.

Inflammation is a key factor in developing many diseases due to its complex pathogenesis. While Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) targeting Cyclooxygenase-2 (COX-2) demonstrate therapeutic efficacy, their clinical utility is limited by significant adverse effects, including myocardial infarction, gastrointestinal disturbances, and abdominal discomfort. Notably, Origanum majorana has demonstrated anti-inflammatory properties, but its bioactive constituents targeting (COX-2) remain unexplored. In this study, we employed a structure-based pharmacophore model using the crystal structure of Human Cyclooxygenase-2 (COX-2; PDB ID: 5F1A) to virtually screen 283 phytochemicals from O. majorana. Molecular docking and interaction analyses revealed three promising compounds (Diosmetin, Arbutin, and Phenyl glucoside) as potential (COX-2) inhibitors, exhibiting strong binding affinities. Pharmacokinetic profiling, encompassing absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment, as well as drug-likeness evaluation, revealed favorable properties for these compounds. To evaluate their binding stability, (100 ns) molecular dynamics (MD) simulations were performed, analyzing root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), hydrogen bonds, solvent-accessible surface area (SASA), and principal component analysis (PCA). Binding free energies calculated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) demonstrated superior affinity for Diosmetin (–37.21 kcal/mol), Arbutin (–23.16 kcal/mol), and Phenyl glucoside (–20.23 kcal/mol) compared to the reference ligand (–16.8 kcal/mol). Additionally, density functional theory (DFT) calculations assessed electronic properties, including HOMO-LUMO energy gaps, global reactivity descriptors, and molecular electrostatic potential, further supporting their potential as (COX-2) inhibitors. Our integrated computational approach identifies these phytochemicals as promising (COX-2) inhibitors, warranting further experimental validation through in vitro and in vivo studies to assess their potential as natural anti-inflammatory therapeutics.