Dual Inhibitors of c-MET and EGFR in Triple Negative Breast Cancer: Pharmacophore Modeling and Molecular Dynamics Based in Silico Drug Repositioning.

Background: The cross-talk between mesenchymal-epithelial transition factor (c-MET) and epidermal growth factor receptor (EGFR) plays a role in breast cancer (BC) progression and resistance to various targeted therapies. Consequently, the simultaneous overexpression of c-MET and EGFR in triple-negative breast cancer (TNBC) is associated with poorer clinicopathological outcomes and increased risks. Despite the development of new c-MET and EGFR inhibitors, the high cost of these drugs makes them inaccessible to most patients. Objectives: Our study investigated the therapeutic potential of existing drugs by repurposing small molecules against these two receptors. Methods: A database of 2028 small molecule agents was screened using pharmacophore-based virtual screening protocols. To rank the compounds, Gibbs free binding energies were used to analyze their binding energies and interactions with these two receptors. Results: It was determined that ARR-4 and ADHHRRR-1 represented the most validated pharmacophore models for c-MET and EGFR, respectively, using receiver operating characteristic (ROC), enrichment factor (EF)1%, and Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC) scores. As a result, eight small molecules were proposed as potential dual inhibitors of c-MET and EGFR, with pasireotide showing the highest affinity for both. According to our analysis of molecular dynamic simulations, pasireotide, the most energetically favorable compound, is proposed as a dual inhibitor of c-MET and EGFR. Conclusions: Considering pasireotide's potential to target c-MET and EGFR pathways, our findings provide a strong rationale for its further preclinical validation in the treatment of TNBC. The demonstrated efficacy and safety of pasireotide in this aggressive subtype of cancer can now be evaluated through subsequent studies.