In silico mutagenesis and modeling of decoy peptides targeting CIB1 to obscure its role in triple-negative breast cancer progression

Breast cancer is a common malignancy in women which is a diverse disease. In women, 287,850 and males, 2710 cases are reported in 2022. Breast cancer is the most often diagnosed disease in women and one of the leading causes of cancer mortality. Approximately 10-20% of all new cases of breast cancer diagnosed in the United States in 2017 were triple-negative breast cancers (TNBCs), which lack the expression of estrogen receptors (ER), and progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). Calcium integrin-binding protein1 lacks a suitable pocket that could be used to create a chemical inhibitor, and because the breast cancer-causing protein is nearly identical to its necessary, wild-type counterparts, it was thought to be druggable. At the present, peptide inhibitors were designed against CIB1. The crystal structure CIB1 in complex with peptide inhibitor UNC10245092 was retrieved from the protein databank. The protein directly blocks interaction with RAF and diminishes signaling through the RAF– MEK–ERK signaling pathway. The goal of this study is to design novel peptides from the reference peptide (UNC10245092) through residue scan methodology. The top five designed peptides (based on binding free energies) were subjected to molecular dynamics simulations using AMBER to evaluate stability. Our results indicate that amongst the top five selected peptides, mutant 2 nd mutant have strong interactions with CIB1 than the reference peptide (UNC10245092) and have the potency to prevent the binding of RAF and CIB1.