Akmal Arina, Javaid Anam, Hussain Riaz, Kanwal Asma, Zubair Muhammad, Ashfaq Usman Ali
Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.
Aziz Fatima Teaching Hospital Faisalabad, Pakistan.
Pak J Pharm Sci. 2019 Nov;32(6(Supplementary)):2823-2828.
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.
转录因子NF-E2 p45相关因子2（NRF2；由NFE2L2编码）及其主要负调节因子E3连接酶衔接蛋白 Kelch样ECH相关蛋白1（KEAP1）对氧化还原、代谢和蛋白质稳态以及炎症的调节有显著作用。因此，NRF2的激活在包括肺部和肝脏慢性疾病、自身免疫性疾病、神经退行性疾病和代谢紊乱以及癌症发生在内的多种病理生理状况下赋予细胞保护作用。本研究的目的是使用分子对接方法筛选植物化学物质库，以鉴定直接抑制Keap1-Nrf2相互作用的植物化学物质。结果，3-（二甲基氨基）-3-亚氨基-N-（4-甲基苯基）丙酰胺、根皮苷、异甘草素、甘草苷和二氢杨梅素等天然化合物被鉴定为Keap1-Nrf2相互作用的直接抑制剂，这从其高结合亲和力以及对Klech结构域特定结合位点的占据情况可以明显看出。因此，这些植物化学物质可被认为能提高细胞对氧化应激的抵抗力，表明它们具有作为抗氧化剂的潜力。此外，所选化合物符合Lipinski规则并具有适当的ADMET性质，增强了其功效。然而，这些需要通过实验方法进行验证，以确保其安全性和有效性。
