The Design of an Enzyme Inhibitor for TGF-beta 1 by Xavier L.

The object of this project is to design an enzyme inhibitor for the the enzyme TGF-beta 1 (transforming growth factor beta 1). The design of this inhibitor will improve upon those of other TGF-beta 1 inhibitors that have already been developed, and will do so by optimizing the inhibitor’s potency, solubility, cell membrane permeability, and selectivity. TGF-beta 1 is a cytokine that is involved in cell growth, cell proliferation, and apoptosis. It helps regulate the cell cycle at the end of the gap 1 phase by preventing the cell from growing further. However, in oncogenic cells, TGF-beta 1 is often over expressed, affecting certain biochemical pathways within the body. Thus, inhibiting TGF-beta 1 has been considered as a possible cancer treatment. The ideal outcome of this project would be to develop an inhibitor that can potentially be tested as a treatment for cancer. The first objective of this project will to be to understand the structure of TGF-beta 1. Using the RCSB Protein Data Bank, TGF-beta 1 can be searched and the different aspects of its structure can be examined. The RCSB Protein Data Bank shows different types of affinities and interactions taking place within the protein, which can help determine how an inhibitor may dock to the protein.The next step would be to determine the site at which the inhibitor would be designed to inhibit TGF-beta 1. It would be necessary to determine whether the inhibition site would be at the active site or an allosteric site. If it were to be at an allosteric site, it would be necessary to determine whether the inhibitor would be designed as an uncompetitive or noncompetitive inhibitor. Such decisions will be determined upon further analysis of the protein TGF-beta 1 structure in the RCSB Protein Data Bank interface. After the inhibition site is determined, the actual design of the inhibitor would begin using a certain type of ligand design software, which can be chosen from the database Click2Drug [3]. Using the information on the structure of TGF-beta 1 from the RCSB Protein Data Bank, the inhibitor would be designed to optimize potency, solubility, cellular permeability, and selectivity. Our design would be created by modifying different side groups of previously designed TGF-beta 1 inhibitors, and determining the combination of side chains that are optimal. After designing the inhibitor, its docking
 to TGF-beta 1 would be simulated using molecular docking software in reference [3]. Based on the success of the simulated docking, the design of the inhibitor could be modified and tested again. If the inhibitor shows enough promise
 in the molecular docking simulations to be tested in real life, its efficacy would be tested be tested in vitro, if possible. It would be ideal if a laboratory could test the inhibitor’s potency, solubility, cellular permeability, and selectivity.