Neurologically Potent Molecules from Crataegus oxyacantha; Isolation, Anticholinesterase Inhibition, and Molecular Docking

Abstract

Crataegus oxyacantha is an important herbal supplement and famous for its antioxidant potential. The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer's disease. The compounds isolated from C. oxyacantha were evaluated for cholinesterases inhibitory activity using Ellman's assay with Galantamine as standard drug. Total of nine (1-9) compounds were isolated. Compounds 1 and 2 were isolated for the first time from natural source. Important natural products like β-Sitosterol-3-O-β-D-Glucopyranoside (3), lupeol (4), β-sitosterol (5), betulin (6), betulinic acid (7), oleanolic acid (8), and chrysin (9) have also been isolated from C. oxyacantha. Overall, all the compounds exhibited an overwhelming acetylcholinesterase (AChE) inhibition potential in the range 5.22-44.47 μM. The compound 3 was prominent AChE inhibitor with IC₅₀ value of 5.22 μM. Likewise, all the compounds were also potent in butyrylcholinesterase (BChE) inhibitions with IC₅₀s of up to 0.55-15.36 μM. All the compounds, except 3, were selective toward BChE. Mechanism of the inhibition of both the enzymes were further studied by docking procedures using Genetic Optimization for Ligand Docking suit v5.4.1. Furthermore, computational blood brain barrier prediction of the isolated compounds suggest that these are BBB+.

Keywords: Alzheimer’s disease; Crataegus oxyacantha; acetylcholinesterase (AChE) inhibition; butyrylcholinesterase (BChE) inhibition; molecular docking; pharmacokinetic properties.

FIGURE 1

Isolated organic molecules from dichloromethane fraction of aerial parts of Crataegus oxyacantha.

FIGURE 2

Superimposed ribbon diagram of the top-scoring docking pose for isolated compound 3-TcAChE (PDB ID 1EVE, red ribbons) and 3-hAChE complex (PDB ID 4EY6, green ribbon).

FIGURE 3

(A) Stereoview of the docking pose of β-Sitosterol-3-O-β-D-Glucopyranoside (3), (blue color stick model) in the binding pocket of AChE (1EVE). (B) Two dimensional (2D) interactions of β-Sitosterol-3-O-β-D-Glucopyranoside (3). Conventional hydrogen bonding interactions are depicted in green and hydrophobic interactions in light pink (Prepared by using Discovery Studio Visualizer).

FIGURE 4

Putative binding mode of 3 in the binding cavity of human AchE (PDB Code 4EY6). The structure reveals that compound 3 is embedded in the binding pocket of galantamine.

FIGURE 5

(A) Stereoview of the docking pose of Betulinic acid (7, blue color stick model) in the binding pocket of AChE (1EVE). (B) 2D interactions of betulinic acid (7).

FIGURE 6

Docked binding pose of the most active isolated compound β-sitosterol (5) in the binding pocket of BChE (magenta color stick model); Surface diagram (a) and Ribbon (b) as rendered by Chimera 1.11.2rc. (c) 2D interactions of (5). Conventional hydrogen bonding interactions are depicted in green and hydrophobic interactions in red (Prepared by using Discovery Studio Visualizer).