Computational Drug Repurposing for Targeting the BRCA1 BRCT Domain in Breast Cancer: Insights from Virtual Screening and Molecular Dynamics Simulations

Background: Mutations in the BRCA1 gene significantly contribute to hereditary breast cancer, primarily by disrupting its role in DNA damage repair. The BRCT domain (PDB ID: 1T15) of BRCA1 is particularly crucial for maintaining genomic integrity, making it a compelling target for therapeutic intervention. Objective: This study aimed to identify potential FDA-approved drugs capable of binding effectively to the mutated BRCA1 (1T15) receptor using structure-based virtual screening and molecular dynamics simulations. Methods: The BRCA1 BRCT domain structure was refined using PDB-REDO, enhancing its stereochemical quality and validation scores. Virtual screening was conducted using DrugRep against a library of 91 FDA-approved compounds. The top hits were evaluated for protein-ligand interactions and subjected to molecular dynamics analysis via iMODS, including deformability, B-factor, covariance matrices, and Eigenvalue -based assessments. Results: Refinement led to substantial improvements in model quality metrics, including rotamer normality (from the 52nd to the 91st percentile) and bump severity (from the 16th to the 76th percentile). The top-scoring compound, Ponatinib, showed a strong binding affinity of –8.9 kcal/mol and formed stable interactions within the largest cavity (834 ų). MD simulations confirmed the stability and flexibility of the complex, highlighting functionally dynamic regions and potential long-range interactions essential for ligand-induced conformational changes. Conclusion: The study underscores the effectiveness of integrating protein structure refinement, virtual screening, and molecular dynamics for rapid drug repurposing. Compounds like Ponatinib exhibit strong potential for targeting mutated BRCA1 in breast cancer, warranting further experimental validation.