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In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)
journal contribution
posted on 2016-11-01, 00:00 authored by Anna E Lohning, Wolf MarxWolf Marx, Liz IsenringGingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale). These compounds have demonstrated in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor is not fully understood although research indicates they may bind to a currently unidentified allosteric binding site. Using in silico techniques, such as molecular docking and GRID analysis, we have characterized the recently available murine 5-HT3 receptor by identifying sites of strong interaction with particular functional groups at both the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. These were assessed concurrently with the top-scoring poses of the docked ligands and included key active gingerols, shogaols and dehydroshogaols as well as competitive antagonists (e.g. setron class of pharmacologically active drugs), serotonin and its structural analogues, curcumin and capsaicin, non-competitive antagonists and decoys. Unexpectedly, we found that the ginger compounds and their structural analogs generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues. We have identified new residues important for binding the ginger compounds. Overall, the results suggest that the ginger compounds and their structural analogues possess a high binding affinity to both sites. Notwithstanding the limitations of such theoretical analyses, these results suggest that the ginger compounds could act both competitively or non-competitively as has been shown for palonosetron and other modulators of CYS loop receptors.
History
Journal
Journal of molecular graphics and modellingVolume
70Pagination
315 - 327Publisher
ElsevierLocation
Amsterdam, The NetherlandsPublisher DOI
ISSN
1093-3263eISSN
1873-4243Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2016, Elsevier Inc.Usage metrics
Keywords
GingerAntiemeticGingerolShogaolsChemotherapy induced nausea vomitingCINVAllosteric SiteAmino Acid SequenceAnimalsBinding SitesCapsaicinComputer SimulationInhibitory Concentration 50LigandsMiceMolecular Docking SimulationProtein SubunitsReceptors, Serotonin, 5-HT3Sequence AlignmentSerotoninSingle-Domain AntibodiesScience & TechnologyLife Sciences & BiomedicineTechnologyPhysical SciencesBiochemical Research MethodsBiochemistry & Molecular BiologyComputer Science, Interdisciplinary ApplicationsCrystallographyMathematical & Computational BiologyComputer ScienceCHEMOTHERAPY-INDUCED NAUSEAGATED ION CHANNELSPUNGENT CONSTITUENTSNICOTINIC RECEPTORSINDUCED EMESISBINDING-SITESLIGANDRECOMBINANTPOTENTIATIONSELECTIVITYComputer Software
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