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Molecules 2019, 24(5), 987; https://doi.org/10.3390/molecules24050987

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

1
Posgrado en Ciencias Químico Biológicas, Facultad de Química, Universidad Autónoma de Querétaro, Cerro de las Campanas S/N, Querétaro C.P. 76010, Mexico
2
Laboratorio de Investigación Química y Farmacológica de Productos Naturales, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro 76010, Mexico
3
Laboratorio de Diseño Asistido por Computadora y Síntesis de Fármacos, Facultad de Química, Universidad Autónoma de Querétaro, Centro Universitario, Querétaro 76010, Mexico
*
Author to whom correspondence should be addressed.
Received: 5 February 2019 / Revised: 5 March 2019 / Accepted: 8 March 2019 / Published: 11 March 2019
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Recently, our research group demonstrated that uvaol and ursolic acid increase NO and H2S production in aortic tissue. Molecular docking studies showed that both compounds bind with high affinity to endothelial NO synthase (eNOS) and cystathionine gamma-lyase (CSE). The aim of this study was to identify hits with high binding affinity for the triterpene binding-allosteric sites of eNOS and CSE and to evaluate their vasodilator effect. Additionally, the mechanism of action of the most potent compound was explored. A high-throughput virtual screening (HTVS) of 107,373 compounds, obtained from four ZINC database libraries, was performed employing the crystallographic structures of eNOS and CSE. Among the nine top-scoring ligands, isoxsuprine showed the most potent vasodilator effect. Pharmacological evaluation, employing the rat aorta model, indicated that the vasodilation produced by this compound involved activation of the NO/cGMP and H2S/KATP signaling pathways and blockade of α1-adrenoceptors and L-type voltage-dependent Ca2+ channels. Incubation of aorta homogenates in the presence of isoxsuprine caused 2-fold greater levels of H2S, which supported our preliminary in silico data. This study provides evidence to propose that the vasodilator effect of isoxsuprine involves various mechanisms, which highlights its potential to treat a wide variety of cardiovascular diseases. View Full-Text
Keywords: high-throughput virtual screening; isoxsuprine; NO/cGMP and H2S/KATP pathways; calcium channels; vasodilation high-throughput virtual screening; isoxsuprine; NO/cGMP and H2S/KATP pathways; calcium channels; vasodilation
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Medina-Ruiz, D.; Erreguin-Luna, B.; Luna-Vázquez, F.J.; Romo-Mancillas, A.; Rojas-Molina, A.; Ibarra-Alvarado, C. Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels. Molecules 2019, 24, 987.

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