{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:53:44Z","timestamp":1792518824103,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Prince Sattam bin Abdulaziz University","award":["PSAU\/2023\/R\/1444"],"award-info":[{"award-number":["PSAU\/2023\/R\/1444"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM\/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand\u2013residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand\u2013protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies.<\/jats:p>","DOI":"10.3390\/molecules28166003","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T10:52:40Z","timestamp":1691664760000},"page":"6003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Modulation of NRF2\/KEAP1-Mediated Oxidative Stress for Cancer Treatment by Natural Products Using Pharmacophore-Based Screening, Molecular Docking, and Molecular Dynamics Studies"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8695-6852","authenticated-orcid":false,"given":"Abdulrahim A.","family":"Alzain","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rua M.","family":"Mukhtar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihal","family":"Abdelmoniem","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tagyedeen H.","family":"Shoaib","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wadah","family":"Osman","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Prince Sattam bin Abdulaziz University, Alkharj 11942, Saudi Arabia"},{"name":"Department of Pharmacognosy, Faculty of Pharmacy, University of Khartoum, Khartoum 11115, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0208-2658","authenticated-orcid":false,"given":"Marwa","family":"Alsulaimany","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed K. B.","family":"Aljohani","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara A.","family":"Almadani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiaan H.","family":"Alsaadi","sequence":"additional","affiliation":[{"name":"Department of Clinical Services, Pharmaceutical Care Services, King Salman Medical City, MOH, Al-Madinah Al-Munawwarah 11176, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam M.","family":"Althubyani","sequence":"additional","affiliation":[{"name":"Department of Clinical Services, Pharmaceutical Care Services, King Salman Medical City, MOH, Al-Madinah Al-Munawwarah 11176, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaimaa G. A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, British University, El Sherouk City, Suez Desert Road, Cairo 11837, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2971-6008","authenticated-orcid":false,"given":"Gamal A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6858-7560","authenticated-orcid":false,"given":"Sabrin R. 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