| Autor: |
Zeder-Lutz, G. (Gabrielle), Choulier, L. (Laurence), Besse, M. (Marie), Cousido-Siah, A. (Alexandra), Ruiz Figueras, F. (Francesc Xavier) ., Didier, B. (Bruno), Jung, M. (Marie-Louise) ., Podjarny, A. (Alberto), Altschuh, D. (Daniele) |
| Jazyk: |
angličtina |
| Rok vydání: |
2011 |
| Předmět: |
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| Popis: |
We investigated the suitability of surface plasmon resonance (SPR) for providing quantitative binding information from direct screening of a chemical library on protein tyrosine phosphatase 1b (PTP1B). The experimental design was established from simulations to detect binding with K(D) < 10(-)(4) M. The 1120 compounds (cpds) were injected sequentially at concentrations [C(cpd)] of 0.5 or 10 muM over various target surfaces. An optimized evaluation procedure was applied. More than 90% of cpds showed no detectable signal in four screens. The 30 highest responders at C(cpd)=10 muM, of which 25 were selected in at least one of three screens at C(cpd)=0.5 muM, contained 22 promiscuous binders and 8 potential PTP1B-specific binders with K(D) ~10(-)(5) M. Inhibition of PTP1B activity was assayed and confirmed for 6 of these, including sanguinarine, a known PTP1B inhibitor. C(cpd) dependence studies fully confirmed screening conclusions. The quantitative consistency of SPR data led us to propose a structure-activity relationship (SAR) model for developing selective PTP1B inhibitors based on the ranking of 10 arylbutylpiperidine analogs. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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