Virtual Screening of Potential In Silico Hits for the Prevention of Neuroinflammation: Arylalkanoic Acid Derivatives of NSAIDs as Selective Dual Inhibitors of Microsomal Prostaglandin E Synthase-2 (mPGES-2) and 5-Lipoxygenase-Activating Protein (FLAP)

Abstract

The aim of this in silico study was the identification of NSAID’s amides with ability to bypass the COX inhibition and selectively target mPGES-2 and FLAP. Molecular binding analysis was conducted on selected compounds using molecular docking, MD simulations and MM/GBSA calculations to assess their potential in the prevention of neuroinflammation. Ligand-based virtual screening was performed in the ChEMBL database, thereby 196 compounds were obtained. Resulting compounds were passed through the BBB permeability and druglikeness filters, and six compounds were selected for further analysis. Molecular docking analysis showed that compounds 4 and 6 can avoid the COX inhibition and simultaneously target mPGES-2 and FLAP. These two top docked compounds were subjected to MD simulations, which indicated that complexes of compound 4 with mPGES-2 and FLAP have shown conformational stability throughout the simulation. Calculated MM/GBSA binding energies confirmed that compound 4 demonstrated dual binding affinity against mPGES-2 and FLAP. Based on the docking score, MM/GBSA average binding energy and MD results, compound 4 emerged as the best in silico hit for the prevention of neuroinflammation.