Pharmacophore-guided repurposing of fibrates and retinoids as GPR40 allosteric ligands with activity on insulin release |
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| Authors: | Erika Cione Maria Cristina Caroleo Hiroyuki Kagechika Fabrizio Manetti |
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| Affiliation: | aDepartment of Pharmacy, Health and Nutritional Sciences (Department of Excellence 2018-2022), University of Calabria, Rende, Italy;bInstitute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Tokyo, Japan;cDepartment of Biotechnology, Chemistry and Pharmacy (Department of Excellence 2018-2022), University of Siena, Siena, Italy |
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| Abstract: | 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). |
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| Keywords: | Virtual screening pharmacophore model drug repurposing GPR40 insulin secretion |
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