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While thymoquinone (TQ) modulates this axis, its efficacy is limited by low potency and poor drug\u2010likeness. We utilized an integrated in silico workflow\u2014including validated QSAR modeling (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.68,\n                    <jats:italic>Q<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sub>ext<\/jats:sub>\n                    \u2009=\u20090.66), ADMET profiling, docking, 200\u2009ns molecular dynamics, and MM\u2013PBSA analysis\u2014to identify improved TQ\u2010derived Keap1 inhibitors. Screening 64 analogs prioritized three leads (CHEMBL3416163, CHEMBL4636830, and CHEMBL221598) with favorable safety and blood\u2013brain barrier permeability. Docking and dynamics confirmed these analogs form stable interactions with Kelch domain hotspots. MM\u2013PBSA calculations revealed significantly enhanced binding free energies (\u221275.10 to \u221293.79\u2009kJ\u2009mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) compared to parent TQ (\u221221.05\u2009kJ\u2009mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    ), driven primarily by van der Waals and hydrophobic forces. This study identifies structurally tractable TQ analogs with improved predicted potency and establishes a robust computational framework for neuroprotective discovery. The prioritized leads are compelling candidates for in vitro and in vivo validation as redox\u2010modulating agents in ALS.\n                  <\/jats:p>","DOI":"10.1002\/open.70286","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:59:38Z","timestamp":1787115578000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1\u2013Nrf2 Pathway for Amyotrophic Lateral Sclerosis Therapy"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5927-1675","authenticated-orcid":false,"given":"Jabir C.","family":"Nalicho","sequence":"first","affiliation":[{"name":"Department of Chemistry Dar es Salaam University College of Education  Dar es Salaam Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petro 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