Design of novel BRC1A target inhibitors: Docking simulation, QSAR modeling, MD simulation and Pharmacokinetics profiling

Breast cancer is the leading recurrent cancer in female, second in mortality, with 1.3 million annual cases, demanding effective interventions. In this study, novel benzoylhydrazone analogs as BRC1A target inhibitors were proposed based on the structure-based design approach. Compound 26 emerged as the template, exhibiting the highest binding affinities of -102.47 and -87.059 kcal/mol. The inhibitive activity of the molecules was predicted using a developed QSAR model, which demonstrated strong statistical performance. The model achieved an internal correlation coefficient (R²) of 0.823, an adjusted R² (R²adj) of 0.779, a cross-validation coefficient (Q²cv) of 0.508, and an external prediction correlation coefficient (R²pred) of 0.643. Seven novel compounds were designed by incorporating amide, hydroxyl, unsubstituted, and methyl-substituted amino groups into the core structure. These new derivatives exhibited better affinities, ranging from -112.148 to -124.542 kcal/mol and -87.627 to -99.128 kcal/mol, surpassing the template. Furthermore, these compounds showed enhanced activity, with pIC 50 values ranging from 7.480 to 10.499, compared to the template's pIC 50 of 6.138. Molecular dynamics simulations confirmed better interactions of these molecules to the BRC1A target. Pharmacological assessments suggested compliance with the drug-like filters, indicating favorable pharmacological and oral safety profiles. Overall, these compounds exhibit promising characteristics as potential BRC1A inhibitors, warranting further investigation.