Combination of human acetylcholinesterase and serum albumin sensing surfaces as highly informative analytical tool for inhibitor screening
Copyright © 2018 Elsevier B.V. All rights reserved..
In the continuous research for potential drug lead candidates, the availability of highly informative screening methodologies may constitute a decisive element in the selection of best-in-class compounds. In the present study, a surface plasmon resonance (SPR)-based assay was developed and employed to investigate interactions between human recombinant AChE (hAChE) and four known ligands: galantamine, tacrine, donepezil and edrophonium. To this aim, a sensor chip was functionalized with hAChE using mild immobilization conditions to best preserve enzyme integrity. Binding affinities and, for the first time, kinetic rate constants for all drug-hAChE complexes formation/disruption were determined. Inhibitors were classified in two groups: slow-reversible and fast-reversible binders according to respective target residence time. Combining data obtained on drug-target residence time with data obtained on serum albumin binding levels, a good correlation with potency, plasma protein binding in vivo, and administration regimen was found. The outcomes of this work demonstrated that the developed SPR-based assay is suitable for the screening, the binding affinity ranking and the kinetic evaluation of hAChE inhibitors. The method proposed ensures a simpler and cost-effective assay to quantify kinetic rate constants for inhibitor-hAChE interaction as compared with other proposed and published methods. Eventually, the determination of residence time in combination with preliminary ADME studies might constitute a better tool to predict in vivo behaviour, a key information for the research of new potential drug candidates.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:155 |
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| Enthalten in: |
Journal of pharmaceutical and biomedical analysis - 155(2018) vom: 05. Juni, Seite 177-184 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fabini, Edoardo [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.09.2018 Date Revised 02.12.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jpba.2018.03.060 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM282839372 |
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| 100 | 1 | |a Fabini, Edoardo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Combination of human acetylcholinesterase and serum albumin sensing surfaces as highly informative analytical tool for inhibitor screening |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Revised 02.12.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2018 Elsevier B.V. All rights reserved. | ||
| 520 | |a In the continuous research for potential drug lead candidates, the availability of highly informative screening methodologies may constitute a decisive element in the selection of best-in-class compounds. In the present study, a surface plasmon resonance (SPR)-based assay was developed and employed to investigate interactions between human recombinant AChE (hAChE) and four known ligands: galantamine, tacrine, donepezil and edrophonium. To this aim, a sensor chip was functionalized with hAChE using mild immobilization conditions to best preserve enzyme integrity. Binding affinities and, for the first time, kinetic rate constants for all drug-hAChE complexes formation/disruption were determined. Inhibitors were classified in two groups: slow-reversible and fast-reversible binders according to respective target residence time. Combining data obtained on drug-target residence time with data obtained on serum albumin binding levels, a good correlation with potency, plasma protein binding in vivo, and administration regimen was found. The outcomes of this work demonstrated that the developed SPR-based assay is suitable for the screening, the binding affinity ranking and the kinetic evaluation of hAChE inhibitors. The method proposed ensures a simpler and cost-effective assay to quantify kinetic rate constants for inhibitor-hAChE interaction as compared with other proposed and published methods. Eventually, the determination of residence time in combination with preliminary ADME studies might constitute a better tool to predict in vivo behaviour, a key information for the research of new potential drug candidates | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acetylcholinesterase inhibitors | |
| 650 | 4 | |a Human recombinant acetylcholinesterase | |
| 650 | 4 | |a Human serum albumin | |
| 650 | 4 | |a Kinetic rate constants | |
| 650 | 4 | |a Residence time | |
| 650 | 4 | |a Surface plasmon resonance | |
| 650 | 7 | |a Cholinesterase Inhibitors |2 NLM | |
| 650 | 7 | |a Enzymes, Immobilized |2 NLM | |
| 650 | 7 | |a Indans |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Piperidines |2 NLM | |
| 650 | 7 | |a Recombinant Fusion Proteins |2 NLM | |
| 650 | 7 | |a Serum Albumin |2 NLM | |
| 650 | 7 | |a Galantamine |2 NLM | |
| 650 | 7 | |a 0D3Q044KCA |2 NLM | |
| 650 | 7 | |a Tacrine |2 NLM | |
| 650 | 7 | |a 4VX7YNB537 |2 NLM | |
| 650 | 7 | |a Edrophonium |2 NLM | |
| 650 | 7 | |a 70FP3JLY7N |2 NLM | |
| 650 | 7 | |a Donepezil |2 NLM | |
| 650 | 7 | |a 8SSC91326P |2 NLM | |
| 650 | 7 | |a Acetylcholinesterase |2 NLM | |
| 650 | 7 | |a EC 3.1.1.7 |2 NLM | |
| 700 | 1 | |a Tramarin, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Bartolini, Manuela |e verfasserin |4 aut | |
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