Computational Analysis of Structure and Binding Energy for the Development of a Cisplatin-Loaded Protein Nanocarrier

Platinum-based drugs, such as cisplatin, are first-line chemotherapy treatments for patients with cancer. However, the success of these drugs is balanced with severe off-target toxicities and high dosing requirements, prompting the development of selective nanocarriers for targeted drug delivery. This study uses a computationally guided approach to examine the role of amino acids in cisplatin binding within proteins as nanocarriers. Using density functional theory, we quantify the binding of cisplatin to platinum-coordinating amino acids. We then rationally engineer a model MSH6 protein carrier, and evaluate the ability of MSH6 to bind cisplatin via molecular docking simulations. Structure predictions of the engineered MSH6 show that inserting the cisplatin-binding site has a limited impact on the nearby protein architecture of MSH6. Finally, we confirm and reveal cisplatins mechanism of action with DNA binding, and compare the energetic potentials of DNA binding from protein-delivered cisplatin to systemically administered cisplatin. Future studies will use these results to experimentally validate the binding of cisplatin in model protein carriers, and inform the strategic design and experimental development of a protein nanocarrier to achieve targeted drug delivery in cancer. TOC Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=60 SRC="FIGDIR/small/699809v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@feee4org.highwire.dtl.DTLVardef@ccc34org.highwire.dtl.DTLVardef@328cd3org.highwire.dtl.DTLVardef@bb8335_HPS_FORMAT_FIGEXP M_FIG C_FIG