Computational Insights into the Binding Mechanism of L6I with Keap1 Kelch Domain (5FNU): A Molecular Docking Approach

Reactive oxygen species (ROS) play a crucial role in cellular homeostasis, and their dysregulation is linked to various diseases, including cancer and neurodegenerative disorders. The Keap1-Nrf2 pathway is a key regulator of oxidative stress response, making Keap1 a promising therapeutic target. In this study, we performed molecular docking of the Keap1 Kelch domain (PDB ID: 5FNU) with the small molecule inhibitor L6I to evaluate its binding affinity and potential as a lead compound. Oxidative stress plays a pivotal role in various pathological conditions, including cancer and neurodegenerative diseases. The Keap1-Nrf2 pathway is a major regulator of oxidative stress response, making Keap1 inhibition a promising therapeutic strategy. However, identifying potent small-molecule inhibitors remains a challenge. The docking grid was centered at (13.928, 64.543, and 28.247) with dimensions (50 × 50 × 50), an exhaustiveness of 32, an energy range of 3, and 8 docking modes. The best binding mode exhibited a binding affinity of -10.6 kcal/mol, indicating strong interaction with Keap1. PyMOL revealed a deviation of 2.677 Å, confirming stable binding within the active site. These results suggest that L6I effectively interacts with Keap1, potentially disrupting its interaction with Nrf2. In conclusion, the molecular docking analysis highlights L6I as a promising candidate for inhibiting Keap1 and modulating oxidative stress pathways. Further experimental validation is required to confirm its therapeutic potential. Keywords: Keap1, Nrf2, oxidative stress, molecular docking, AutoDock, PyMOL, small molecule inhibitors.