The Use of High-Throughput Virtual Screening Software in the Proposal of A Novel Treatment for Congenital Heart Defects

• Main Author: Suh, Caitlin D
• Format: Others
• Published: Scholarship @ Claremont 2019
• Subjects: High-throughput virtual screening; chemistry; drug discovery; PyRx; screening; Dance; Medicinal Chemistry and Pharmaceutics; Other Chemicals and Drugs; Other Chemistry
• Online Access: https://scholarship.claremont.edu/cmc_theses/2260; https://scholarship.claremont.edu/cgi/viewcontent.cgi?article=3184&context=cmc_theses

Conventional screening of potential drug candidates through wet lab affinity experiments using libraries of thousands of modified molecules is time and resource consuming, along with the fact that it contributes to the widening time gap between the discovery of disease-causing mutations and the implementation of resulting novel treatments. It is necessary to explore whether the preliminary use of high-throughput virtual screening (HTVS) software such as PyRx will curb both the time and money spent in discovering novel treatments for diseases such as congenital heart defects (CHDs). For example, AXIN2, a protein involved in a negative feedback loop inhibiting the Wnt/β-catenin signaling pathway important for cardiogenesis, has recently been associated with CHD. The loss-of-function mutation L10F on the tankyrase-binding domain of AXIN2 has been shown to upregulate the pathway by loss of inhibition ability, leading to the accumulation of intracellular β-catenin. In a different paper, however, AXIN2 has been shown to be stabilized using XAV-939, a small-molecule drug which targets tankyrase. PyRx and VMD will be used to modify the drug in order to increase its binding affinity to AXIN2, stabilizing the protein and reinstating its inhibitory property to treat CHDs. When used in adjunction to wet lab experiments, HTVS software may decrease costs and the time required to bring a potentially life-saving treatment into use.