Modeling the Binding of Salinosporamide A (MZB) to the Human 20S Proteasome for Potential Cancer Treatment

Modeling the Binding of Salinosporamide A (MZB) to the Human 20S Proteasome for Potential Cancer Treatment

Alvin Sherman Library

This project aims to model and observe the binding of the drug Marizomib (MZB) and compare its binding affinity other similar drugs to the proteosome using the PDB ID 9HMN and bioinformatics tools. MZB is an anti-cancer drug that was derived from the marine bacterium, Salinosporamide A. Its function is to inhibit the human 20S proteasome from breaking down excess proteins, causing the cell to trigger apoptosis. Additionally, MZB has the ability to cross the blood-brain barrier and utilize three catalytically active amino acid sites. The existing PDB ID (9HMN) of a 20S proteasome with MZB bound was 3D printed. The catalytically inactive alpha subunits and one beta ring were removed, and subunits were color coded. To compare the binding of MZB to that of the similar drug Carfilzomib (CFZ), we used SwissDock to isolate the beta-5 subunit and dock Carilzomib in an MZB affinitive area. It was concluded that MZB and CFZ have similar binding regions, though at different residues. MZB has a greater affinity for the β1, β2, and β5 subunits, while the CFZ binds only to the β5 site. It was determined that MZB binds to the three catalytic residues on the three subunits. The process of modeling MZB and the use of a model helps illustrate its potential for cancer treatments. MZB bins to all three active subunits within the beta-ring, which is something that other drugs cannot do effectively. Furthermore, MZB is stabilized by binding to the conserved triad and other residues for structural integrity.