In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

Abstract

. In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale).. Retrieved from http://dx.doi. org/10.1016/j.jmgm.2016.10.008 1 Abstract Gingerols 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. KeywordsGinger antiemetic Zingiber officinale gingerol shogaols chemotherapy induced nausea vomiting 2

Capsaicin Is a Negative Allosteric Modulator of the 5-HT3 Receptor

“…All binding poses of capsazepine are located at the interface between transmembrane domain (TMD) and extra cellular domain. This binding site is situated in similar position with allosteric binding site predicted by ( Lohning et al, 2016 ). Free energy of binding predicted by Autodock Vina for most favorable docking pose is −7.8 kcal/mol.…”

“…Grid center was designated x, y, z dimensions: 139.00, 219.00 and 273.00. These coordinates correspond to allosteric binding site of 5HT 3 receptor for ginger compounds identified in an earlier study ( Lohning et al, 2016 ) on human 5HT 3 receptor. Docking calculations were performed using the Lamarckian genetic algorithm (LGA) ( Morris et al, 1998 ).…”

“…Thus, the results of electrophysiological, luminescence, and radioligand binding experiments indicate that capsaicin acts as an allosteric inhibitor of 5-HT 3 receptor. Importantly, in a recent in silico docking study, a high scoring allosteric and hydrophobic capsaicin binding site located at the interface between the extracellular and transmembrane domain of 5-HT 3A receptor subunit has been identified ( Lohning et al, 2016 ). Our results are also in agreement with an earlier study investigating the effects of more than 200 odorous compounds, terpenes, alcohols, and pungent substances ( Ziemba et al, 2015 ), reporting that various gingerol derivatives, capsaicin and polygodial, inhibit 5-HT 3 receptors.…”

Natural Negative Allosteric Modulators of 5-HT3 Receptors

“…As a consequence, this process reduces the 5-HT 3A blocking activity of ginger [57]. Although all data showed that ginger-derived molecules act allosterically, in silico techniques showed that these compounds can also bind to the orthosteric binding site causing competitive inhibition as well [110]. Ginger extracts were also tested against other ion channels such as L-type Ca 2+ , Na + and K + channels.…”

Antiallodynic effect induced by [6]‐gingerol in neuropathic rats is mediated by activation of the serotoninergic system and the nitric oxide–cyclic guanosine monophosphate–adenosine triphosphate‐sensitive K+ channel pathway

“…Also, gingerols and shangols could interact with the human serotonin 5‐HT 1A receptor with moderated binding affinities (Ki = 3–20 μM), suggesting a partially agonist for this receptor (Nievergelt, Huonker, Schoop, Altmann, & Gertsch, ). Moreover, ginger compounds have demonstrated in vitro 5‐HT 3 receptor antagonism (Lohning, Marx, & Isenring, ). It is widely known that activation of the 5‐HT 3 receptor produced a pronociceptive effect (Hoyer et al, ).…”