Title of presentation: Using Molecular Docking and Dynamics Simulations to Characterize the Inhibitory Activity of Compound 41 Against the Thioesterase Domain of Fatty Acid Synthase
Presenter: Matthew Kidd
Advisor: Paul Baures, PhD
 
Abstract:
Upregulation of Fatty Acid Synthase (FAS) provides cancer with a near constant supply of fatty acids, enabling cancer cells to divide uncontrollably. This makes the FAS enzyme an attractive target for cancer therapy. In 2019, Lupien et al. identified an inhibitor of the FAS thioesterase (FAS-TE) domain starting with a high throughput screening (compound 1, C1), and rational design to improve its plasma stability and cytotoxicity (compound 41, C41). However, the potency of compound 41 will have to be improved before it can be efficacious at tolerable doses. This could be done with the guidance of structural information about the binding complex, but there is no published experimental structure of the FAS-C41 complex to date. To rectify this, we created a model of the FAS-C41 complex by using SwissDock to identify possible binding modes of C41 against an FAS-TE PDB model (3TJM, 1.48 A). We also docked Biotin against Streptavidin (4BX6, 1.59 A) as a control experiment to assess the accuracy of the SwissDock software. We have reason to believe that at least one of our top 10 ligand poses has an RMSD within 2.5 A of the correct binding pose, meaning that it might form a stable complex with the FAS-TE enzyme during a 100 ns Molecular Dynamics simulation (which we plan to run in the future). Finally, based on the data we collected, we hypothesized about the intermolecular forces that guide FAS-C41 binding, and speculated as to what could improve the potency of the C41 compound.