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.
|Conference||MM2017 Molecular Modelling Conference|
|Period||27/09/17 → 29/09/17|