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Drug resistance

The drug cisplatin is widely used to treat testicular cancer, ovarian cancer, cervical cancer, colorectal cancer and relapsed lymphoma. Its beneficial effects stems from its binding to DNA in cancerous cells, causing cell apoptosis. Unfortunately, the clinical efficiency of cisplatin is severely limited by the emergence of resistance. This is associated with a reduced cellular accumulation of the drug, related, among other factors, to the altered activity of some proteins involved in the maintenance of copper homeostasis and able to bind cisplatin. In particular, the high-affinity copper transporter Ctr1 is believed to mediate the uptake of cisplatin, whereas the copper chaperone Atox1 and copper pumps ATP7A/ATP7B are believed to mediate the efflux/sequestration of cisplatin. Characterizing the molecular mechanisms underlying uptake, efflux, and sequestration processes is a key step to understand drug resistance and eventually set up a pharmacological strategy to counter-act them.
In this context, our group is strongly involved in predicting the possible binding modes of cisplatin to the copper transporter proteins involved in drug resistance (see for instance Fig. 3 for the binding modes of cisplatin to Ctr1). To achieve this goal, we use a set of computational tools including hybrid DFT-based Car-Parrinello QM/MM simulations, force matching approaches, replica exchange MD and, most importantly, computational spectroscopy. This approach provides the fundamental quantities (NMR chemical shifts, EXAFS, IR, CD spectra, etc.) that, compared with the experiments, allow us to test the reliability of the binding models and discriminate the most probable ones. This study is performed in collaboration with the bioinorganic chemistry group headed by Prof. Giovanni Natile at University of Bari (Italy). This research is supported by a DFG grant.

Cancer Ctr1Binding of cisplatin to the extracellular binding domain of Ctr1: simulated structures (Nguyen et al. J. Chem. Theory Comput. 2012, 8, 2912).


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