Quantum Chemical Studies and Pharmacophore Modeling for Designing Novel Keap1 Antagonists that Enhance Nrf2 Mediated Neuroprotection

In recent years, the significance of oxidative stress in the pathophysiology of Neurodegenerative/developmental diseases like Attention Deficit Hyperactivity Disorder, Parkinson’s and Alzheimer’s is being studied at an accelerating pace. Nrf2 activation via Keap1 inhibition is an established strategy for enhancing the activity of the cellular antioxidant mechanism. In this study pharmacophore modeling was employed to design efficient Keap1 inhibitors from well-known polypharmacological phytochemicals after extensive structural modifications to improve their pharmacodynamic, pharmacokinetic and drug-likeness qualities. Quantum chemical calculations at the B3LYP/6-31G (d, p) level of theory were performed for geometry optimization of the novel ligands and for computing their electronic properties. Molecular docking studies and comparative interaction analysis ranked the Resveratrol-4 derivative as the best multi-domain antagonist of the Keap1 protein. The following study presents the application of novel, modified, phytochemical derivatives, as efficient antagonists of the Keap1 protein for enhancing neuroprotection from redox insults.