Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H₂S/K
Adenosine Triphosphate
/ metabolism
Adrenergic alpha-1 Receptor Antagonists
/ chemistry
Calcium Channel Blockers
/ chemistry
Cyclic GMP
/ metabolism
Dose-Response Relationship, Drug
High-Throughput Screening Assays
Humans
Hydrogen Sulfide
/ metabolism
Isoxsuprine
/ chemistry
Metabolic Networks and Pathways
/ drug effects
Molecular Docking Simulation
Molecular Dynamics Simulation
Nitric Oxide
/ metabolism
Quantitative Structure-Activity Relationship
Small Molecule Libraries
Vasodilator Agents
/ chemistry
Workflow
NO/cGMP and H2S/KATP pathways
calcium channels
high-throughput virtual screening
isoxsuprine
vasodilation
Journal
Molecules (Basel, Switzerland)
ISSN: 1420-3049
Titre abrégé: Molecules
Pays: Switzerland
ID NLM: 100964009
Informations de publication
Date de publication:
11 Mar 2019
11 Mar 2019
Historique:
received:
05
02
2019
revised:
05
03
2019
accepted:
08
03
2019
entrez:
14
3
2019
pubmed:
14
3
2019
medline:
22
6
2019
Statut:
epublish
Résumé
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/K
Identifiants
pubmed: 30862086
pii: molecules24050987
doi: 10.3390/molecules24050987
pmc: PMC6429095
pii:
doi:
Substances chimiques
Adrenergic alpha-1 Receptor Antagonists
0
Calcium Channel Blockers
0
Small Molecule Libraries
0
Vasodilator Agents
0
Nitric Oxide
31C4KY9ESH
Adenosine Triphosphate
8L70Q75FXE
Cyclic GMP
H2D2X058MU
Isoxsuprine
R15UI3245N
Hydrogen Sulfide
YY9FVM7NSN
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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