Molecular Modeling Strategies to Probe Modulation of NADPH Oxidase 2 (NOX2) in Ischemic Stroke

Abstract

Excessive amounts of reactive oxygen species (ROS) may contribute to oxidative stress which is the fundamental mechanism of cell-damaging in cerebral ischemic stroke. NADPH oxidases 2 (NOX2) being the primary cause of ROS generation has been originally recognized in immune cells and plays a significant role in the phagocytosis of microbes. Thus, inhibition of NOX2 might represent a promising strategy for ischemic stroke therapy. The prediction of inhibitors that target specifically NOX2 is essential as NOX1 shares 56% sequence similarity with NOX2. In the current work, ligand and structure-based studies were applied to probe the 3D structural features of NOX2 and NOX1 modulators. The binding hypothesis of the NOX2 modulator has been proposed by already known modulators of NOX2 core domain through molecular docking studies. Additionally, GRIND (Grid independent descriptors) based study of NOX2 indicated that two Hydrogen bond donors at a mutual distance of 1.6-2.0Å, two hydrogen bond acceptor at a distance of 1.6-2.0Å, and two molecular shape-based feature at a mutual distance of 12.40-12.80Å positively contributed to activity against NOX2. Similarly, GRIND model of NOX2 selective datasets depicted two molecular shape-based feature at a mutual distance of 4.00-4.80Å, hydrophobic and shape based feature at a mutual distance of 4.00-4.40 Å were favourable for activity against most potent inhibitor of NOX2. GRIND model for NOX1 illustrated that two molecular shaped based feature at a mutual distance of 4.80-5.20Å were present in most potent inhibitors of NOX1. Further, we developed the pharmacophore model based on docking studies as complemented by protein ligand interactions for both NOX2 and NOX1 isoforms. These pharmacophore models predicted the liability of new chemical compounds as selective NOX2 inhibitors after virtual screening of drug bank compounds. Mainly, five potential hits have been predicted through virtual screening namely the carbamazepine, 1-n-(4-sulfamoylphenyl-ethyl)-2, 4, 6- trimethylpyridinium, BMS-911543, Pranoprofen, and 4-(6-{[(4-methylcyclohexyl) amino] methyl}-1,4-dihydroindeno[1,2-c] pyrazol-3-yl) benzoic acid. The outcome of the current project can be further extended through experimental validation of identified hits.