article · Molecules
Oxidative stress is a key driver in the progression of cancer. Activating the Nrf2 antioxidant pathway by disrupting its interaction with Keap1 presents an attractive therapeutic route. Computational screening was employed to identify natural products that can bind to the Kelch domain of KEAP1. Starting from a structure-based pharmacophore model that retrieved thousands of initial matches, molecular docking and binding energy calculations narrowed the selection to ten top-performing candidates. Three specific compounds were chosen for detailed assessment: ZINC000002123788, ZINC000002111341, and ZINC000002125904. These molecules showed favourable interactions with vital residues in the binding pocket alongside favourable drug-like profiles during property evaluation. Further hundred-nanosecond molecular dynamics simulations confirmed that the complexes remained stable throughout, highlighting these natural molecules as prospective candidates for cancer therapy targeting KEAP1.
Oxidative damage contributes heavily to the onset and development of tumours. By computationally identifying natural compounds that reactivate the body's natural antioxidant pathways via KEAP1 inhibition, researchers gain promising starting points for designing safer, targeted cancer treatments that rely on natural product chemistry.
This work identifies early-stage lead candidates for pharmaceutical developers focused on oncology and antioxidant therapeutics. Because the findings are strictly computational, including molecular docking and dynamics simulations, the compounds represent early discovery research and require extensive in vitro validation and preclinical testing before any commercial development.
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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-residue 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-protein 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.
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DOI: 10.3390/molecules28166003
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