In silico investigation into the interactions between murine 5-HT3receptor and the principle active compounds of ginger (Zingiber officinale).
Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale). These compounds have demonstrated in vitro to exert 5-HT3receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV). The site and mechanism of action by which these compounds interact with the 5-HT3receptor 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-HT3receptor 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.
Faculty of Health Sciences & Medicine, Bond University, Gold Coast, 4229, Australia. Electronic address: alohning@bond.edu.au.
Anna E
AE
Lohning
Faculty of Health Sciences & Medicine, Bond University, Gold Coast, 4229, Australia. Electronic address: wmarx@bond.edu.au.
Wolfgang
W
Marx
Faculty of Health Sciences & Medicine, Bond University, Gold Coast, 4229, Australia. Electronic address: lisenrin@bond.edu.au.
Liz
L
Isenring
D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002211:Capsaicin / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D020939:Zingiber officinale / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D012701:Serotonin / Q000737:chemistry; D061905:Single-Domain Antibodies / Q000737:chemistry
D008024:Ligands; D021122:Protein Subunits; D044406:Receptors, Serotonin, 5-HT3; D061905:Single-Domain Antibodies; D012701:Serotonin; D002211:Capsaicin
Antiemetic; CINV; Chemotherapy induced nausea vomiting; Ginger; Gingerol; Shogaols