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Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect

Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulati...

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Autores principales: Domínguez-Mendoza, Elix Alberto, Galván-Ciprés, Yelzyn, Martínez-Miranda, Josué, Miranda-González, Cristian, Colín-Lozano, Blanca, Hernández-Núñez, Emanuel, Hernández-Bolio, Gloria I., Palomino-Hernández, Oscar, Navarrete-Vazquez, Gabriel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913794/
https://www.ncbi.nlm.nih.gov/pubmed/33557136
http://dx.doi.org/10.3390/molecules26040799
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author Domínguez-Mendoza, Elix Alberto
Galván-Ciprés, Yelzyn
Martínez-Miranda, Josué
Miranda-González, Cristian
Colín-Lozano, Blanca
Hernández-Núñez, Emanuel
Hernández-Bolio, Gloria I.
Palomino-Hernández, Oscar
Navarrete-Vazquez, Gabriel
author_facet Domínguez-Mendoza, Elix Alberto
Galván-Ciprés, Yelzyn
Martínez-Miranda, Josué
Miranda-González, Cristian
Colín-Lozano, Blanca
Hernández-Núñez, Emanuel
Hernández-Bolio, Gloria I.
Palomino-Hernández, Oscar
Navarrete-Vazquez, Gabriel
author_sort Domínguez-Mendoza, Elix Alberto
collection PubMed
description Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.
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spelling pubmed-79137942021-02-28 Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect Domínguez-Mendoza, Elix Alberto Galván-Ciprés, Yelzyn Martínez-Miranda, Josué Miranda-González, Cristian Colín-Lozano, Blanca Hernández-Núñez, Emanuel Hernández-Bolio, Gloria I. Palomino-Hernández, Oscar Navarrete-Vazquez, Gabriel Molecules Article Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation. MDPI 2021-02-04 /pmc/articles/PMC7913794/ /pubmed/33557136 http://dx.doi.org/10.3390/molecules26040799 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Domínguez-Mendoza, Elix Alberto
Galván-Ciprés, Yelzyn
Martínez-Miranda, Josué
Miranda-González, Cristian
Colín-Lozano, Blanca
Hernández-Núñez, Emanuel
Hernández-Bolio, Gloria I.
Palomino-Hernández, Oscar
Navarrete-Vazquez, Gabriel
Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
title Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
title_full Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
title_fullStr Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
title_full_unstemmed Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
title_short Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
title_sort design, synthesis, and in silico multitarget pharmacological simulations of acid bioisosteres with a validated in vivo antihyperglycemic effect
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913794/
https://www.ncbi.nlm.nih.gov/pubmed/33557136
http://dx.doi.org/10.3390/molecules26040799
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