Molecular Insights Into N ⁴ HDPP Derivatives as Potential MTDH–SND1 Interaction Inhibitors in Metastatic Breast Cancer: A Combined Docking, Molecular Dynamics, MEP, and ADME‐T Study

ABSTRACT Metastatic breast cancer represents a significant global health challenge. Disruption MTDH‐SND1 interaction has emerged as an effective approach for targeting breast cancer. In this work, SDN1 structure was selected for computational analysis using a series of N4HDPP derivatives as SDN1 predicted inhibitors through in silico approaches, including molecular docking, MMGBSA rescoring, MEP study, MD simulations, and ADME‐T properties. MTDH peptide was extracted from SND1‐MTDH structure, and chosen as a reference for these derivatives. Interestingly, compounds 14, 18, 12, and 13 obtained the most favorable Vina scores, ranging from −7.6 to −8.0 kcal mol − 1 , indicating stronger predicted binding within the SND1 pocket relative to the other screened N4HDPP compounds and better than the co‐crystallized ligand C‐26‐A2 (−6.6 kcal mol −1 ). The quantitative MEP analysis was performed as comparative study to predict the main N4HDPP interactions. Six molecular dynamics simulations at 100 ns were carried out for the hits along with references; all trajectory analyses (RMSD, RMSF, Rg, SASA, distance analysis, and MMPBSA) validate the stability of the selected systems. Indeed according to ADME‐T predictions, all molecules showed a rather favorable drug‐likeness profile. Our research unveils that compounds: 12, 13, 14, and 18 as potential competitors of MTDH and inhibitors of SND1, establishing a robust groundwork for disrupting the MTDH‐SND1 interaction and advancing cancer drug discovery.