Screening of phytochemicals against KEAP1- NRF2 interaction to reactivate NRF2 Functioning: Pharmacoinformatics based approach

Abstract

The transcription factor NF- E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch- like ECH-associated protein 1 (KEAP1), significantly contribute to regulation of redox, metabolic and protein homeostasis, as well as inflammation. Therefore, activation of NRF2 imparts cytoprotective effect in numerous pathophysiological conditions including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders and cancer initiation. The objective of this study was to screen library of phytochemicals to identify phytochemicals for direct inhibition of the Keap1–Nrf2 interaction using molecular docking approach. As a result, natural compounds such as 3-(Dimethylamino)-3-imino-N-(4-methylphenyl) propanamide, Phlorizin, Diffutin, Liquiritin and Dihydrogenistin were identified as direct inhibitors of the Keap1–Nrf2 interaction, as evident from its high binding affinity and occupancy of specific binding sites of Klech domain. Thus these phytochemical could be proposed to improve cell resistance to oxidative stress, suggesting their potential as antioxidants. Moreover, the selected compounds fulfilled the Lipinksi rule and appropriate ADMET properties potentiating its efficacy. However, these need to be validated through experimental approaches to ensure its safety profile and efficacy.