New targets for an old drug |
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Authors: | Leticia M Toledo-Sherman Leroi Desouza Christopher M Hosfield Linda Liao Kelly Boutillier Paul Taylor Shane Climie Linda McBroom-Cerajewski Michael F Moran |
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Institution: | (1) MDS Proteomics Inc., 251 Attwell Drive, M9W 7H4 Toronto, ON, Canada |
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Abstract: | Methotrexate has been a clinical agent used in cancer, immunosuppression, rheumatoid arthritis and other highly proliferative
diseases for many years, yet its underlying molecular mechanism of action in these therapeutic areas is still unclear. We
present a chemical proteomics approach that uses ultra-sensitive mass spectrometry coupled to an inverse protein-ligand docking
computational technique to unravel the mechanism of action of this drug. Using methotrexate tethered to a solid support we
were able to isolate a signficant number of proteins. We effectively captured a large portion of the de novo purine metaolome and propose a pathway architecture similar to that seen in signaling pathways and consistent with substrate
channeling. More importantly, we were able to capture protein targets that could potentially provide new insights into the
mechanism of action of methotrexate in rheumatoid arthritis and immunosuppression. The application of this approach to other
drugs and drug candidates may facilitate the prediction of unknown and secondary therapeutic target proteins and those related
to the side effects and toxicity. These results demonstrate that this proteomics technology could play an important role in
drug discovery and development since it allows monitoring of the interactions between a drug and the protein content of a
cell. |
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Keywords: | Methotrexate targets mechanism of action chemical proteomics pharmaco-proteomics metabolome inverse docking substrate channeling |
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