Fig 1.
Structures of bacoside A saponin glycosides and aglycones.
Bacoside A is a mixture of bacoside A3, bacopaside II, bacopaside X and bacopasaponin C. These bacosides are dammarane-type triterpenoid saponins that have three sugar chains linked to a nonpolar triterpene aglycone skeleton.
Fig 2.
Formation of ebelin lactone and bacogenin A1.
Bacoside A components form aglycone jujubogenin and pseudojujubogenin through deglycosylation and further acid hydrolysis yields ebelin lactone and bacogenin A1.
Table 1.
Summary of radioligand receptor binding assay components and reactions according to each receptor.
Table 2.
Total number of conformations in a cluster and binding energy of compounds for 5-HT1A, 5-HT2A, D1, D2 and M1 receptors and AChE (in complex with fasciculin or donepezil) enzyme.
Table 3.
The physicochemical properties of bacopasaponin C, bacopaside X, bacopaside II, bacoside A3, jujubogenin, pseudojujubogenin, ebelin lactone and bacogenin A1.
Fig 3.
BBB penetration and intestinal absorption properties by ADMET descriptors.
(A) bacoside A3, (B) bacopaside II, (C) bacopasaponin C, (D) bacopaside X, (E) jujubogenin, (F) pseudojujubogenin, (G) bacogenin A1, (H) tacrine, (I) donepezil and (J) ebelin lactone. Tacrine and donepezil were used as standard orally active CNS drugs. ADMET prediction level for Human intestinal absorption (HIA)- 0 (good), 1 (moderate), 2 (poor), 3 (very poor); Blood brain barrier (BBB)- 0 (very high penetrant), 1 (high), 2 (medium), 3 (low) and 4 (undefined). The aglycones and its acid hydrolysis derivatives showed better intestinal absorption and BBB penetration compared to the parent bacosides.
Table 4.
CNS receptor binding affinities of bacosides and aglycones.
Fig 4.
Docking of the ebelin lactone to (A) the M1 mAChR and (B) the 5-HT2A models.
Iperoxo (sphere) from the crystal structure of M2 mAChR (PDB code: 4MQS) was used to show the orthosteric site in the M1 mAChR, and the transparent surface represents the orthosteric site of the 5-HT2A receptor. Ebelin lactone bound to a cavity directly above the orthosteric site suggesting it could be an allosteric modulator. For the purpose of clarity, some of the loops and transmembrane helix are not shown.
Fig 5.
2-D interaction map of ebelin lactone in complex with the M1 mAChR model.
Negatively-charged, polar and hydrophobic residues are depicted with red, light blue and green circles, respectively. The hydrogen bond between the OH group at position-3 and Y85 residue is indicated by a purple dashed arrow. Ebelin lactone established non-polar interactions with L183, Y82 and L86 (non-conserved residues) which are postulated to be responsible for the allosteric subtype selectivity in muscarinic receptors.
Fig 6.
Superposition of ebelin lactone (blue) in complex with the M1 mAChR model and LY2119620 (green) in complex with the M2 mAChR.
Superposition of the crystal structure of the allosteric modulator LY2119620 in complex with M2 mAChR (PDB code: 4MQS) with the docked ebelin lactone in M1 mAChR shows the overlapping binding positions of these ligands, suggesting ebelin lactone could be a M1 allosteric modulator. Iperoxo is shown in spheres to depict the orthosteric site of the receptor.
Fig 7.
2-D interaction map of ebelin lactone in complex with the 5-HT2A receptor model.
Negatively-charged, polar and hydrophobic residues are depicted with red, light blue and green circles, respectively. Ebelin lactone is coordinated by a set of residues only through non-polar interactions.
Fig 8.
Superposition of ebelin lactone (cyan) in complex with the 5-HT2A receptor and TAK-875 (green) in complex with free-fatty acid receptor 1.
A. Front view and B. Top view (from the extracellular surface). Superposition of ebelin lactone in complex with the 5-HT2A receptor from the docking studies and the allosteric modulator TAK-875 in complex with the free-fatty acid receptor 1 from the crystal structure (PDB code: 4PHU) shows both ligands bound to cavities in between the transmembrane helices suggesting ebelin lactone could be a 5-HT2A allosteric modulator. The transparent surface represents the orthosteric site of the 5-HT2A receptor. For the purpose of clarity, some of the loops and transmembrane helix are not shown.