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

doi:10.3390/molecules26040799

Open AccessArticle

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

by

Elix Alberto Domínguez-Mendoza

¹,

Yelzyn Galván-Ciprés

¹,

Josué Martínez-Miranda

¹,

Cristian Miranda-González

¹,

Blanca Colín-Lozano

¹,

Emanuel Hernández-Núñez

²

,

Gloria I. Hernández-Bolio

²

,

Oscar Palomino-Hernández

^3,4 and

Gabriel Navarrete-Vazquez

^1,*

¹

Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209, Mexico

²

Cátedra CONACyT, Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados, IPN, Unidad Mérida, Yucatan 97310, Mexico

³

Computational Biomedicine (IAS-5/INM-9), Forschungszentrum Juelich, 52425 Julich, Germany

⁴

Department of Chemistry, Rheinisch-Westfälische Technische Hochschule Aachen, 52425 Aachen, Germany

^*

Author to whom correspondence should be addressed.

Molecules 2021, 26(4), 799; https://doi.org/10.3390/molecules26040799

Submission received: 5 January 2021 / Revised: 31 January 2021 / Accepted: 2 February 2021 / Published: 4 February 2021

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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Abstract

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.

Keywords: multitarget ligands; drug design; diabetes; molecular dynamics

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MDPI and ACS Style

Domínguez-Mendoza, E.A.; Galván-Ciprés, Y.; Martínez-Miranda, J.; Miranda-González, C.; Colín-Lozano, B.; Hernández-Núñez, E.; Hernández-Bolio, G.I.; Palomino-Hernández, O.; Navarrete-Vazquez, G. Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect. Molecules 2021, 26, 799. https://doi.org/10.3390/molecules26040799

AMA Style

Domínguez-Mendoza EA, Galván-Ciprés Y, Martínez-Miranda J, Miranda-González C, Colín-Lozano B, Hernández-Núñez E, Hernández-Bolio GI, Palomino-Hernández O, Navarrete-Vazquez G. Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect. Molecules. 2021; 26(4):799. https://doi.org/10.3390/molecules26040799

Chicago/Turabian Style

Domínguez-Mendoza, Elix Alberto, Yelzyn Galván-Ciprés, Josué Martínez-Miranda, Cristian Miranda-González, Blanca Colín-Lozano, Emanuel Hernández-Núñez, Gloria I. Hernández-Bolio, Oscar Palomino-Hernández, and Gabriel Navarrete-Vazquez. 2021. "Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect" Molecules 26, no. 4: 799. https://doi.org/10.3390/molecules26040799

APA Style

Domínguez-Mendoza, E. A., Galván-Ciprés, Y., Martínez-Miranda, J., Miranda-González, C., Colín-Lozano, B., Hernández-Núñez, E., Hernández-Bolio, G. I., Palomino-Hernández, O., & Navarrete-Vazquez, G. (2021). Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect. Molecules, 26(4), 799. https://doi.org/10.3390/molecules26040799

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

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