Pharmacophore-guided repurposing of fibrates and retinoids as GPR40 allosteric ligands with activity on insulin release
A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 β-cells with EC50 in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC50 values were 5.6, 21, and 14 nM, respectively).
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Journal of enzyme inhibition and medicinal chemistry - 36(2021), 1 vom: 16. Dez., Seite 377-383 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cione, Erika [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.06.2021 Date Revised 18.01.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1080/14756366.2020.1864629 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM32086975X |
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| 245 | 1 | 0 | |a Pharmacophore-guided repurposing of fibrates and retinoids as GPR40 allosteric ligands with activity on insulin release |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 15.06.2021 | ||
| 500 | |a Date Revised 18.01.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 β-cells with EC50 in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC50 values were 5.6, 21, and 14 nM, respectively) | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a GPR40 | |
| 650 | 4 | |a Virtual screening | |
| 650 | 4 | |a drug repurposing | |
| 650 | 4 | |a insulin secretion | |
| 650 | 4 | |a pharmacophore model | |
| 650 | 7 | |a Aniline Compounds |2 NLM | |
| 650 | 7 | |a FFAR1 protein, human |2 NLM | |
| 650 | 7 | |a Fibric Acids |2 NLM | |
| 650 | 7 | |a Insulin |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Propionates |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
| 650 | 7 | |a Retinoids |2 NLM | |
| 650 | 7 | |a efaproxiral |2 NLM | |
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| 650 | 7 | |a Bezafibrate |2 NLM | |
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| 700 | 1 | |a Caroleo, Maria Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Kagechika, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Manetti, Fabrizio |e verfasserin |4 aut | |
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