Computational Characterization of MAP2K3 Mutations in Breast Cancer: Implications for Targeted Therapy Design

ABSTRACT Mitogen‐activated protein kinase kinase 3 (MAP2K3) mutations have recently gained attention for their potential role in breast cancer progression and therapy resistance. In this study, we investigated the structural and functional consequences of four MAP2K3 missense mutations, A55T, R67W, S39P, and T193M, identified through whole‐exome sequencing (WES) of breast cancer samples. Using an integrative computational workflow that combined molecular docking, WES‐driven mutational annotation, and molecular dynamics (MD) simulations, we evaluated how these mutations influence MAP2K3 stability and inhibitor interaction. Docking analyses revealed a notable reduction in MAP2K3–PP242 (P2X) inhibitor binding affinity, with the A55T variant showing the largest decline. MD simulations further indicated that A55T induces significant structural destabilization in the inhibitor‐bound state, which may impair drug engagement. Conversely, although T193M retained overall structural stability, it displayed altered intramolecular interactions and increased conformational fluctuations that could influence MAP2K3 activity. Collectively, these mutation‐driven perturbations suggest a compromised therapeutic response to MAP2K3‐targeted inhibitors. Our findings provide mechanistic insight into how specific MAP2K3 alterations may contribute to breast cancer biology and drug resistance and establish a computational framework for prioritizing and designing next‐generation inhibitors. Future experimental validation will be essential to confirm these computational predictions and guide personalized therapeutic strategies.