In silico insights into dual COX inhibition by fluoro-substituted indole derivative using DFT, molecular docking, and MD simulation studies

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.