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Srinidhi_Preprint_V3.pdf (5.91 MB)
Quantum Chemical Studies and Pharmacophore Modeling for Designing Novel Keap1 Antagonists that Enhance Nrf2 Mediated Neuroprotection
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
revised on 13.10.2020 and posted on 14.10.2020by . Srinidhi
In recent years, the significance of oxidative stress in the pathophysiology of Neurodegenerative/developmental disorders 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 improving 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 (BBB > 0.9, HIA > 0.85). Density functional theory-based quantum chemical calculations at the B3LYP/6-31G (d, p) level of theory were performed for the geometry optimization of the novel ligands and for computing their electronic properties. Resveratrol-4 was found to be the most desirable candidate with and ΔE = 4.24497 eV. HOMO and LUMO distribution of the Resveratrol-4 was found to be very favourable for keap1 binding. Molecular docking studies and comparative interaction analysis also ranked the Resveratrol-4 derivative as the best multi-domain antagonist of the Keap1 protein with a binding affinity of -8 kcal/mole. The following study presents the application of Resveratrol-4 a novel, modified, phytochemical derivative, as an efficient antagonist of the Keap1 protein for enhancing nrf2 mediated neuroprotection from redox insults.