In silico insights into dual <scp>COX</scp> inhibition by fluoro‐substituted indole derivative using <scp>DFT</scp>, molecular docking, and <scp>MD</scp> simulation studies

Abstract The present study investigates the molecular structure, vibrational frequencies, electronic properties, and pharmacological potential of ethyl 6‐fluoro‐1H‐indole‐2‐carboxylate (EFI2C) using a combined experimental and theoretical approach. EFI2C was analyzed as a potential cyclooxygenase (COX) inhibitor with a focus on the co‐inhibition of COX‐1 and COX‐2 enzymes to reduce adverse effects associated with conventional NSAIDs. Molecular docking revealed that EFI2C forms polar hydrogen bonds and hydrophobic interactions with COX‐1 (PDBs 3KK6 and 3N8Y) and COX‐2 (PDBs 1CX2 and 4 M11), indicating strong binding affinities. The lowest‐energy conformer of EFI2C, obtained through potential energy scanning, was re‐optimized using a higher basis set. An excellent agreement between experimental and theoretical vibrational modes has been obtained. Intermolecular hydrogen bonding interactions were characterized using QTAIM and NBO methodologies. Pharmacokinetic analysis revealed a bioavailability score of 0.55, indicating efficient absorption into the bloodstream. Molecular dynamics simulations of the 3N8Y‐EFI2C and 1CX2‐EFI2C complexes for 100 ns confirmed the dynamic stability of the ligand within receptor binding sites. The dual action of EFI2C on COX‐1 and COX‐2 suggests its potential to retain the anti‐inflammatory efficacy of NSAIDs while minimizing gastrointestinal and cardiovascular side effects. This study positions EFI2C as a promising lead compound for the development of safer, more effective nonsteroidal anti‐inflammatory drugs.