Breast cancer is the most common cancer among women in the US, despite recent advancements. Estrogen receptor-positive breast cancer can be treated with estrogen inhibiting drugs, but these only work in 50-80% of tumors as they often become drug-resistant. An alternative drug target is the DNA strand that codes for the tumor-causing protein, preventing the tumor from proliferating. Intercalators are drugs that bind directly to DNA between neighboring base pairs and have the potential to be an improvement upon the current treatments for breast cancer. Lin, et al. (2014) reported an intercalator (XR5944) that binds to a breast cancer-specific DNA sequence at two different points of the TFF1-ERE DNA strand, making it a bis-intercalator, shown in Figure 1. The drug has two weak binding regions on the DNA strand that do not remain bound to the DNA consistently, and there are two strong binding regions that remain bound to the DNA after a significant amount of time. The goal of this project is to computationally modify and improve the binding of XR5944 to the breast cancer-specific DNA sequence by observing trends of nucleic acid movements around the binding site and the contribution of the nucleic acids to the overall free energy of the binding. Data collected from this study has shown improvements to the binding free energy of modified XR5944 through lengthening the central carbon chain of the drug.

Optimization of bisintercalator drug modifications as a treatment for breast cancer utilizing common structural drug design techniques and molecular dynamics

ACS Spring Meeting 2021

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