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Background <p>The KEAP1–NRF2 pathway is a pivotal regulator of cellular antioxidant responses and is implicated in chronic kidney disease (CKD) pathogenesis. Inhibiting KEAP1 to activate NRF2 signaling offers a promising therapeutic strategy.</p> Methods <p>We used the GSE180393 and GSE180394 to evaluate the <i>KEAP1</i> expression in CKD patient. We conducted the PPI network and functional enrichment analysis. We constructed a pharmacophore model based on the KEAP1–IQK co-crystal structure. We performed virtual screening, molecular docking, and ADMET to identify potential drug-like inhibitors. We conducted 200&#xa0;ns molecular dynamics simulations (MDS), MM/GBSA, and per-residue decomposition of KEAP1-ligand complexes. Finally, density functional theory (DFT) analyses were assessed.</p> Results <p><i>KEAP1</i> was significantly overexpressed in glomerular and tubular compartments of CKD patients with high diagnostic efficacy. The KEAP1-interacting PPI network is functionally linked to the KEAP1–NRF2 pathway. Pharmacophore-based virtual screening, molecular docking, and ADMET explored several inhibitors with CPD0297, CPD0298, and CPD0301 showing the most promising profiles. MDS parameters, including RMSD, RMSF, RG, SASA, B<sub>SASA</sub>, average-distance, minimum-distance, number of contacts, hydrogen-bond dynamics, PCA, FEL, DCCM, porcupine plot, correlated-anticorrelated 3D network, and secondary structure analysis, confirmed the stability of KEAP1–ligand complexes. MM/GBSA algorithm estimated binding free energies between -27.27 and -23.26&#xa0;kcal/mol. Per-residue decomposition analysis revealed that the contributed residues to the binding free energy. DFT calculations demonstrated stable electronic properties and reactivity profiles of these ligands.</p> Conclusion <p>We explored CPD0297, CPD0298, and CPD0301 as promising KEAP1 inhibitors, representing lead compounds for the development of targeted therapeutics in the treatment of CKD.</p>

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Integrated Computational Exploration of Novel KEAP1 Inhibitors Targeting the KEAP1–NRF2 Pathway in Chronic Kidney Disease

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • YiRui Wang,
  • Yang Yu,
  • Daiqin Xiong,
  • Rexidan Zaker

摘要

Background

The KEAP1–NRF2 pathway is a pivotal regulator of cellular antioxidant responses and is implicated in chronic kidney disease (CKD) pathogenesis. Inhibiting KEAP1 to activate NRF2 signaling offers a promising therapeutic strategy.

Methods

We used the GSE180393 and GSE180394 to evaluate the KEAP1 expression in CKD patient. We conducted the PPI network and functional enrichment analysis. We constructed a pharmacophore model based on the KEAP1–IQK co-crystal structure. We performed virtual screening, molecular docking, and ADMET to identify potential drug-like inhibitors. We conducted 200 ns molecular dynamics simulations (MDS), MM/GBSA, and per-residue decomposition of KEAP1-ligand complexes. Finally, density functional theory (DFT) analyses were assessed.

Results

KEAP1 was significantly overexpressed in glomerular and tubular compartments of CKD patients with high diagnostic efficacy. The KEAP1-interacting PPI network is functionally linked to the KEAP1–NRF2 pathway. Pharmacophore-based virtual screening, molecular docking, and ADMET explored several inhibitors with CPD0297, CPD0298, and CPD0301 showing the most promising profiles. MDS parameters, including RMSD, RMSF, RG, SASA, BSASA, average-distance, minimum-distance, number of contacts, hydrogen-bond dynamics, PCA, FEL, DCCM, porcupine plot, correlated-anticorrelated 3D network, and secondary structure analysis, confirmed the stability of KEAP1–ligand complexes. MM/GBSA algorithm estimated binding free energies between -27.27 and -23.26 kcal/mol. Per-residue decomposition analysis revealed that the contributed residues to the binding free energy. DFT calculations demonstrated stable electronic properties and reactivity profiles of these ligands.

Conclusion

We explored CPD0297, CPD0298, and CPD0301 as promising KEAP1 inhibitors, representing lead compounds for the development of targeted therapeutics in the treatment of CKD.