2024 AIChE Annual Meeting

Designing a Peptide Ligand for a Novel Cancer Therapeutic

Half a million women die every year with breast cancer, of which 150,000 cases are estimated to be Triple Negative Breast Cancer (TNBC). TNBC is an aggressive type of breast cancer that lacks the Estrogen (ER), Progesterone (PR) and Human Epidermal Growth Factor (HER2) receptors. There is a lack of targeted therapies available for TNBC, as current endocrine and drug therapies that target ER, PR, or HER2 are ineffective. Sigma 2 receptors are overexpressed in proliferative cells and tumors, especially breast cancer cells. Some of the ligands that bind to the receptors are known to have cytotoxic effects. The aim of this study is to computationally randomize amino acid sequences that bind to the sigma 2 receptor to make a cytotoxic drug. By utilizing the Rosetta Scripts software, an XML-like language used for parsing functions within the Rosetta suite, 4,000 different amino acid sequences that bind to this receptor were generated. The top ten unique sequences with the lowest binding energy were then used for further analysis. Using the FlexPepDock docking protocol, PackRotamersMover, and relaxation algorithms, one thousand different amino acid sequences were generated. The top 10 most energetically favorable structures were further analyzed by their Root Mean Square Deviation (RMSD) relative to the top scoring pose to evaluate the potential entropic penalty of adopting the energetically favorable pose. By analyzing the RMSD values and corresponding energy scores, the top three peptides were then chosen to synthesize and characterize to further test for cytotoxicity and affinity.