In silico analysis of the interactions of ginger actives with the serotonin (5-HT3)receptor

Research output: Contribution to conferencePresentationResearch

Abstract

Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale) and have been shown in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV) (Marx, 2015). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor remains unclear although research indicates they may bind at an unidentified allosteric binding site (Pertz, 2011). This preliminary study involved using molecular docking techniques (Surflex-Dock) correlated with GRID analyses for identifying sites of strong interaction between ginger actives and the recently available murine 5-HT3 receptor (Lohning, 2016). We present binding data for the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. Among the top-scoring poses were 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 analogues generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues (Trattnig, 2012). 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. 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 and provide evidence for the efficacy of ginger compounds for treatment of CINV clinically demonstrated in recent trials.
Original languageEnglish
Publication statusUnpublished - Sep 2017
EventMM2017 Molecular Modelling Conference: AMMA (Australian Molecular Modellers Association) - Western Australia, Perth/Margaret River, Australia
Duration: 27 Sep 201729 Sep 2017
https://mm2017.curtin.edu.au/

Conference

ConferenceMM2017 Molecular Modelling Conference
Abbreviated titleMM2017
CountryAustralia
CityPerth/Margaret River,
Period27/09/1729/09/17
Internet address

Fingerprint

Ginger
Receptors, Serotonin, 5-HT3
Computer Simulation
Allosteric Site
Binding Sites
Nausea
Vomiting
Serotonin Agents
Drug Therapy
Curcumin
Capsaicin
Site-Directed Mutagenesis
Serotonin
Ligands

Cite this

Lohning, A. E., Marx, W., & Isenring, E. (2017). In silico analysis of the interactions of ginger actives with the serotonin (5-HT3)receptor. MM2017 Molecular Modelling Conference, Perth/Margaret River, Australia.
Lohning, Anna Elizabeth ; Marx, Wolfgang ; Isenring, Elisabeth. / In silico analysis of the interactions of ginger actives with the serotonin (5-HT3)receptor. MM2017 Molecular Modelling Conference, Perth/Margaret River, Australia.
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Lohning, AE, Marx, W & Isenring, E 2017, 'In silico analysis of the interactions of ginger actives with the serotonin (5-HT3)receptor' MM2017 Molecular Modelling Conference, Perth/Margaret River, Australia, 27/09/17 - 29/09/17, .

In silico analysis of the interactions of ginger actives with the serotonin (5-HT3)receptor. / Lohning, Anna Elizabeth; Marx, Wolfgang; Isenring, Elisabeth.

2017. MM2017 Molecular Modelling Conference, Perth/Margaret River, Australia.

Research output: Contribution to conferencePresentationResearch

TY - CONF

T1 - In silico analysis of the interactions of ginger actives with the serotonin (5-HT3)receptor

AU - Lohning, Anna Elizabeth

AU - Marx, Wolfgang

AU - Isenring, Elisabeth

PY - 2017/9

Y1 - 2017/9

N2 - Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale) and have been shown in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV) (Marx, 2015). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor remains unclear although research indicates they may bind at an unidentified allosteric binding site (Pertz, 2011). This preliminary study involved using molecular docking techniques (Surflex-Dock) correlated with GRID analyses for identifying sites of strong interaction between ginger actives and the recently available murine 5-HT3 receptor (Lohning, 2016). We present binding data for the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. Among the top-scoring poses were 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 analogues generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues (Trattnig, 2012). 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. 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 and provide evidence for the efficacy of ginger compounds for treatment of CINV clinically demonstrated in recent trials.

AB - Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale) and have been shown in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV) (Marx, 2015). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor remains unclear although research indicates they may bind at an unidentified allosteric binding site (Pertz, 2011). This preliminary study involved using molecular docking techniques (Surflex-Dock) correlated with GRID analyses for identifying sites of strong interaction between ginger actives and the recently available murine 5-HT3 receptor (Lohning, 2016). We present binding data for the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain. Among the top-scoring poses were 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 analogues generally outscored other ligands at both sites. Our results correlated well with previous site-directed mutagenesis studies in identifying key binding site residues (Trattnig, 2012). 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. 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 and provide evidence for the efficacy of ginger compounds for treatment of CINV clinically demonstrated in recent trials.

M3 - Presentation

ER -

Lohning AE, Marx W, Isenring E. In silico analysis of the interactions of ginger actives with the serotonin (5-HT3)receptor. 2017. MM2017 Molecular Modelling Conference, Perth/Margaret River, Australia.