Structural investigation of Keap1-Nrf2 protein-protein interaction (PPI) Inhibitors for treating myocarditis through molecular simulations

Myocarditis is classified as an inflammatory disease of the heart muscle which is a leading cause of sudden death. The Keap1-Nrf2 -ARE pathway, a primary defense mechanism of antioxidant stress, is considered as a potential target against myocarditis. To gain insights into the relationship between the activity and structure of the compounds and design superior active novel inhibitors, 3D-QSAR, molecular docking and molecular dynamic (MD) simulation were combined to investigate the interaction between Keap1-Nrf2 PPI inhibitors and Keap1. The comparative molecular field analysis (CoMFA) model (q2= 0.907, n=7, R2= 0.997) and comparative molecular similarity index analysis (CoMSIA) model (q2= 0.900, n=7, R2= 0.993) showed that the built 3D-QSAR models were credible and predictable. Based on these models, 10 new compounds were discovered and their bioactivity was validated using molecular docking and MD simulation. Furthermore, the plausible ADME/T characteristics of new compounds were evaluated and the key residues (Arg415, Tyr334, Ser602, Ser363, Arg380, etc.) in the active site were also identified by ADME/T research and free energy calculation. The binding energy results show that the structurally optimized compounds(N1: -65.409 Kcal/mol, N3: -54.619 Kcal/mol, N4: -62.627 Kcal/mol, N5: -60.903 Kcal/mol, and N8: -66.272 Kcal/mol ) have lower binding free energy values than compound 43 (ΔGbind: -49.991 Kcal/mol ), indicating that they have a better affinity for the target. These findings provide necessary theoretical guidance for the discovery and design of highly active drugs against myocarditis.

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