Direct Keap1-kelch inhibitors as potential drug candidates for oxidative stress-orchestrated diseases: A review on In silico perspective

• Published in: Pharmacological research Vol. 167; p. 105577
• Main Authors: Boyenle, Ibrahim Damilare, Divine, Ukachi Chiamaka, Adeyemi, Rofiat, Ayinde, Kehinde Sulaimon, Olaoba, Olamide Tosin, Apu, Chowdhry, Du, Lei, Lu, Qian, Yin, Xiaoxing, Adelusi, Temitope Isaac
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-05-2021
• Subjects: Animals; Antioxidants - chemistry; Antioxidants - pharmacology; Computer Aided Drug Design (CADD); Drug Design; Drug Discovery; Humans; In silico; Keap1; Kelch-Like ECH-Associated Protein 1 - antagonists & inhibitors; Kelch-Like ECH-Associated Protein 1 - chemistry; Kelch-Like ECH-Associated Protein 1 - metabolism; Models, Molecular; NF-E2-Related Factor 2 - metabolism; Oxidative stress; Oxidative Stress - drug effects; Protein Domains - drug effects; Protein Interaction Maps - drug effects; Protein-protein interaction (PPI); Protein-protein interaction (PPI); Keap1; Oxidative stress; In silico; Computer Aided Drug Design (CADD)
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2021.105577

The recent outcry in the search for direct keap1 inhibitors requires a quicker and more effective drug discovery process which is an inherent property of the Computer Aided Drug Discovery (CADD) to bring drug candidates into the clinic for patient’s use. This Keap1 (negative regulator of ARE master activator) is emerging as a therapeutic strategy to combat oxidative stress-orchestrated diseases. The advances in computer algorithm and compound databases require that we highlight the functionalities that this technology possesses that can be exploited to target Keap1-Nrf2 PPI. Therefore, in this review, we uncover the in silico approaches that had been exploited towards the identification of keap1 inhibition in the light of appropriate fitting with relevant amino acid residues, we found 3 and 16 other compounds that perfectly fit keap1 kelch pocket/domain. Our goal is to harness the parameters that could orchestrate keap1 surface druggability by utilizing hotspot regions for virtual fragment screening and identification of hotspot residues.
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