Doctoral Themes - Proposals

Ruthenium compounds that revert multidrug resistance in cancer therapy

Supervisors

Andreia Valente, amvalente@ciencias.ulisboa.pt

Miguel Machuqueiro, machuque@ciencias.ulisboa.pt

Registration Institution

Faculdade de Ciências (Universidade de Lisboa)

Project description

A severe limitation to the efficacy of the drugs in clinical use for the treatment of cancer is multidrug resistance (MDR). One of the main mechanisms of MDR is the overexpression of membrane transport proteins, such as P-gp and MRP1, that pump drugs out of cells. The BIOIN CQE Research Group has been developing ruthenium organometallic compounds that target these exporters and address this important limitation in chemotherapy. Preliminary results identified the best metallodrug ever reported to inhibit P-gp [1] and that these compounds are cisplatin sensitizers in resistant lung cancer cell lines [2]. Despite these encouraging results, we still lack the molecular details of the interaction between our ruthenium inhibitors and P-gp, which would be pivotal to direct our synthesis efforts. P-gp has a large number of binding sites and undergoes significant conformational changes during the transport process. This movement changes the shape of the protein cavity, which can have a deleterious effect on the success of molecular docking campaigns. This can be circumvented by using molecular dynamics (MD) to study the conformational space of the transport proteins and take advantage of enhanced sampling techniques (steered-MD, umbrella-sampling, meta-dynamics, etc.) to evaluate and complement the docking results. Within this multidisciplinary PhD proposal, we will merge computational (docking and MD) with experimental (rational synthesis of new compounds) studies to unveil the structural features that make these compounds unique and trigger an optimization process to achieve even better chemotherapeutics.

References

[1] L. Côrte-Real et al. Eur. J. Med. Chem., 2019, https://doi.org/10.1016/j.ejmech.2018.12.022

[2] R. Teixeira et al. Inorg. Chem. Front., 2021, https://doi.org/10.1039/D0QI01344G

Keywords

ruthenium; chemotherapy; synthesis; molecular docking; molecular dynamics

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