Desirability function combining metabolic stability and functionality of peptides
| Autor: | Kathelijne Peremans, Simon Vermeire, Antita Adriaens, Sylvia Van Dorpe, Ingeborgh Polis, Bart De Spiegeleer |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Chemistry Organic Chemistry Biological activity Peptide General Medicine Dermorphin Computational biology Blood–brain barrier Biochemistry chemistry.chemical_compound DAMGO medicine.anatomical_structure Structural Biology In vivo Opioid Receptor Binding Drug Discovery medicine Molecular Medicine Opioid peptide Molecular Biology |
| Zdroj: | Journal of Peptide Science. 17:398-404 |
| ISSN: | 1075-2617 |
| Popis: | The evaluation of peptides as potential therapeutic or diagnostic agents requires the consideration of several criteria that are targeted around two axes: functionality and metabolic stability. Most often, a compromise has to be made between these mutually opposing characteristics. In this study, Derringer's desirability function, a multi-criteria decision-making method, was applied to determine the best peptide for opioid studies in a single figure-of-merit. The penetration of the blood-brain barrier (BBB) determines the biological functionality of neuropeptides in the brain target tissue, and consists of an influx and an efflux component. The metabolic stability in the two concerned tissues, i.e. plasma and brain, are taken into consideration as well. The overall selection of the peptide drug candidate having the highest BBB-drugability is difficult due to these conflicting responses as well as the different scalings of the four biological parameters under consideration. The highest desirability, representing the best BBB-drugability, was observed for dermorphin. This peptide is thus the most promising drug candidate from the set of eight opioid peptides that were investigated. The least desirable candidate, with the worst BBB influx and/or metabolic stability, was found to be CTAP. Validation of the desirability function by in vivo medical imaging showed that dermorphin and DAMGO penetrate the BBB, whereas EM-1 and TAPP did not. These results are thus consistent with those obtained with the desirability evaluation. To conclude, the multi-criteria decision method was proven to be useful in biomedical research, where a selection of the best candidate based on opposing characteristics is often required. |
| Databáze: | OpenAIRE |
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