Silibinin: an inhibitor for a high-expressed BCL-2A1/BFL1 protein, linked with poor prognosis in breast cancer.

Breast cancer (BC) accounts for 30% of all diagnosed cases of cancer in women and remains a leading cause of cancer-related deaths among women worldwide. The current study looks for a protein from the anti-apoptotic/pro-survival BCL-2 family whose overexpression reduces survivability in BC patients and a potential inhibitor for the protein. We found BCL-2A1/BFL1 protein with high expression linked to low survivability in BC. The protein shows prognosis in 8 out of 29 categories, whereas no other family member manifests this property. Out of 7379 compounds, three small molecules (CHEMBL9509, CHEMBL2104550 and CHEMBL3545011) form an H-bond with BCL-2A1/BFL1 protein's unique residue Cys55. Of the three small molecules, we found CHEMBL9509 (Silibinin) to be a potent inhibitor. The compound forms a stable H-bond with the residue Cys55 with the lowest binding energy compared to the other two compounds. It remains stable in the BH3 binding region for more than 100 ns, whereas the other two detach from the region. Additionally, the compound is found to be better than Venetoclax and Nematoclax. We firmly believe in the compound CHEMBL9509 potency to halt BC's progression by inhibiting the BCL-2A1/BFL1 protein, increasing patients' survivability.Communicated by Ramaswamy H. Sarma.