Determining a viable in silico method for the identification of protein-protein interaction inhibitors by studying the interactions of netrin-1 DCC and UNC5

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Sturm, Hunter
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Protein-Protein interactions (PPI) are responsible for a wide variety of biological processes. The misregulation of these interactions can often times be deadly as misregulated PPI’s have been known to cause cancer and other life-threatening diseases. That is why, in recent years, more time and energy has been focused on regulating PPI’s. The issue faced in finding small molecule PPI inhibitors however is that PPI interfaces are very large and complex. This makes the discovery of small molecule inhibitors a challenge as the site the molecule will bind is often unknown. Currently the most common method for identifying lead compounds is high throughput screening (HTS). HTS is a costly method however and is heavily dependent on the correct selection of the chemical library. Current libraries are designed for enzyme targets and therefore may not be effective when searching for compounds that bind to the surface of a protein. The study outlined in this thesis aims at developing a more efficient and cost-effective method to test many small molecules against a PPI for their inhibitory properties. The methods used in this study employ in silico library screening to identify potential inhibitors. Once lead compounds are found, biological testing in the form of microscale thermophoresis and nuclear magnetic resonance spectroscopy has been completed to validate the molecular docking results. This work has identified multiple potential inhibitors, and once biotesting occurs if the hits prove valid the method outlined in this thesis will be validated.