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13. D’Andrea, G., 2015. Quercetin: A flavonol with multifaceted
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of endogenous ligands are present. GPR40 is a clinically
validated target in T2DM treatment and from medicinal chemist
viewpoint, more derivatives were synthesized and assayed, but
failed the clinical trials especially for their hepatotoxicity. In this
context, hybrid molecules bearing oleic acid, which is an
endogenous GPR40 ligand, can represent an alternative strategy
to develop GPR40 agonists. Hence, the synthesized quercetin-3-
oleoyl hybrids bind a new pocket of GPR40 receptor highlighting
a possible pharmacological strategy for the management of
T2DM. Molecular docking simulations suggested that both
quercetin derivatives AV1 and AV2 could occupy the same
allosteric binding site hypothesized for the GPR40 antagonist
DC260126 and recently demonstrated to accommodate new
GPR40 allosteric agonists. The finding that AV2 acts as partial
agonist of GPR40 elects this molecule a promising approach in
the therapy of T2DM because of its potential beneficial effect
beyond improvement of insulin secretion.
14. Carullo, G., Aiello, F., 2018. Quercetin-3-oleate. Molbank 3,
M1006.
15. Vasapollo, P., Cione, E., Luciani, F., Gallelli, L., 2018. Generalized
Intense Pruritus During Canagliflozin Treatment: Is it an Adverse
Drug Reaction? Curr. Drug Saf. 13(1), 38-40.
16. Sharma, D., Verma, S., Vaidya, S., Kalia, K., Tiwari, V., 2018.
Recent updates on GLP-1 agonists: Current advancements &
challenges. Biomed Pharmacother. 108, 952-962.
Acknowledgments
17. Ho, J.D., Chau, B., Rodgers, L., Lu, F., Wilbur, K.L., Otto, K.A.,
Chen, Y., Song, M., Riley, J.P., Yang, H., Reynolds, N.A., Kahl,
S.D., Lewis, A.P., Groshong, C., Madsen, R.E., Conners, K.,
Lineswala, J.P., Gheyi, T., Decipulo Saflor, M., Lee, M.R., Benach,
J., Baker, K.A., Montrose-Rafizadeh, C., Genin, M.J., Miller, A.R.,
Hamdouchi, C., 2018. Structural basis for GPCR40 allosteric
agonism and incretin stimulation. Nat. Commun. 9, 1645.
18. Santos, L.R.B., Rebelato, E., Graciano, M.F.R., Abdulkader, F.,
Curi, R., Carpinelli, A.R., 2011. Oleic acid modulates metabolic
substrate channeling during glucose-stimulated insulin secretion via
NAD(P)H oxidase. Endocrinology 152(10), 3614-3621.
19. Srivastava, A., Yano, J., Hirozane, Y., Kefala, G., Gruswitz, F.,
Snell, G., Lane, W., Ivetac, A., Aertgeerts, K., Nguyen, J.,
Jennings, A., Okada, K., 2014. High-resolution structure of the
human GPR40 receptor bound to allosteric agonist TAK-875.
Nature 513, 124-127.
The authors are grateful to Ministero dell’Istruzione,
dell'Università e della Ricerca (MIUR) (Rome) for “Dipartimento
di Eccellenza grant 2018-2022” at both Departments. Santa
Chiara Lab is also acknowledged for the use of the Schrodinger
suite.
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Discovery of TAK-875:
A Potent, Selective, and Orally
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Quercetin/oleic acid-based G-protein-coupled receptor 40 ligands