In silico Exploration of COX-1 Inhibition: A Pharmacophore-Driven Strategy Coupled with Molecular Docking, ADMET Profiling, and MD Simulations

Cyclooxygenase-1 (COX-1) has been implicated in neuroinflammation, particularly in conditions like Alzheimer’s disease, where it is upregulated in activated microglia near inflammatory sites. This suggests the significant role of COX-1 in neurodegenerative processes and positions it as a promising target for therapeutic intervention, with selective COX-1 inhibitors showing potential to reduce neuroinflammation and improve cognitive function. In this study, a chemical feature-based pharmacophore model was developed on the co-crystal ligand (W8M) of COX-1 to conduct the virtual screening of nine commercial databases, resulting in 807 hits that were further subjected to molecular docking to find the binding affinities with COX-1 protein. The binding affinities of the hits were analyzed and compounds in the range of –11.27 to –10.47 kcal mol-1 were selected for further analysis. The ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis filtered out four compounds whose binding poses were analyzed for the protein-ligand complex stability by MD (molecular dynamics) simulation. Simulation results revealed that the selected compounds remained closely bound to protein indicating that they can act as lead compounds to control the biological activity of COX-1. However, further in vitro investigation is required to test the biological efficacy of the reported compounds.