Structure-based identification of small-molecule stabilizers targeting mutant TP53 (Y220C) in breast cancer: a pharmacophore modeling, molecular docking and dynamics study

Background Mutations in TP53, particularly the Y220C variant, destabilize the protein and impair tumor-suppressor function, driving breast cancer progression. Restoring the structural integrity of TP53 Y220C using small-molecule stabilizers represents a potential therapeutic strategy. Methods Pharmacophore modeling based on the co-crystal ligand binding site guided screening of a ligand library using the Pharmit platform. Molecular docking, ADME, and toxicity predictions filtered drug-like and safe candidates. Molecular dynamics simulations (MDS) and per-residue MM/PBSA analyses assessed binding stability, structural fluctuations, and energetic contributions. Results TP53 Y220C was found to be highly expressed in breast cancer. Pharmacophore-guided virtual screening and molecular docking identified several promising compounds with favorable drug-likeness and safety profiles. Among these, three ligands, including CPD0001, CPD0136, and CPD0330, demonstrated stable binding and favorable interactions with the Y220C cavity. Molecular dynamics analyses revealed that CPD0001 and CPD0136 maintained superior structural stability, reduced conformational fluctuations, compact cavity organization, and coordinated residue motions throughout the simulation period, closely resembling the co-crystal ligand. In contrast, CPD0330 demonstrated moderate stabilization with comparatively higher flexibility. MM/PBSA and per-residue energy decomposition analyses further supported the strong binding affinity and stabilizing potential of CPD0001 and CPD0136. CPD0330 showed moderate stabilization comparable to co-crystal ligands. Conclusions Overall, CPD0001 and CPD0136 emerged as promising small-molecule stabilizers capable of reinforcing the TP53 Y220C mutant cavity and maintaining structural stability comparable to the co-crystal ligand. These findings highlight their potential as lead candidates for the development of targeted therapeutics against TP53 Y220C-driven breast cancer.