Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1-Nrf2 Pathway for Amyotrophic Lateral...

Oxidative stress drives neuronal vulnerability in amyotrophic lateral sclerosis (ALS), making the Keap1-Nrf2 pathway a vital therapeutic target. While thymoquinone (TQ) modulates this axis, its efficacy is limited by low potency and poor drug-likeness. We utilized an integrated in silico workflow-including validated QSAR modeling (R² = 0.68, Q² _ext = 0.66), ADMET profiling, docking, 200 ns molecular dynamics, and MM-PBSA analysis-to identify improved TQ-derived Keap1 inhibitors. Screening 64 analogs prioritized three leads (CHEMBL3416163, CHEMBL4636830, and CHEMBL221598) with favorable safety and blood-brain barrier permeability. Docking and dynamics confirmed these analogs form stable interactions with Kelch domain hotspots. MM-PBSA calculations revealed significantly enhanced binding free energies (-75.10 to -93.79 kJ mol^-1) compared to parent TQ (-21.05 kJ mol^-1), 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-modulating agents in ALS.