Pharmacological evaluation and in-silico modeling study of compounds isolated from Ziziphus oxyphylla

Abstract

Medicines derived from plants are preferred over synthetic therapeutic agents in treating different diseases. Ziziphus oxyphylla (a member of Rhamnaceae family) is a medicinal plant used as a remedy of different diseases in Greek and Ayurveda medical systems. Z. oxyphylla roots were shade dried and then subjected to extraction of bioactive compounds using different solvent systems and silica gel. From ethyl acetate fraction, three compounds viz., p-coumaric acid (V), 3,4-dimethoxy benzoic acid (VI), and 4-heptyloxy benzoic acid (VII) were isolated in pure form. The selection of ethyl acetate fraction for isolation was based on HPLC profiling of crude extract and different fractions. These compounds were characterized by different spectroscopic techniques and evaluated for their in vitro antioxidant, anticholinesterase, α-glucosidase, and α-amylase inhibitory potentials. To find out possible binding interactions of V with AChE and BChE crystals, in-silico docking studies were also carried out. Compound V showed maximum scavenging capabilities of DPPH and ABTS free radicals with IC₅₀ values of 69 and 62 μg/mL respectively. Excellent percent inhibition (83.4 ± 0.5% at highest concentration 1000 μg/mL) of acetylcholinesterase (AChE) was exhibited by compound V (IC₅₀ = 80 μg/mL); whereas, for the mentioned concentration, 83.2 ± 1.1% inhibition (IC₅₀ = 90 μg/mL) of butyrylcholinesterase (BChE) was observed as well. The compound VI exhibited highest % inhibition against α-glucosidase (IC₅₀ = 84 μg/mL) whereas α-amylase was more potently inhibited by compound V (% inhibition = 86.8 % and IC₅₀ = 85 μg/mL). Docking scores of -1.391 Kcal/mol (BChE) and -6.253 Kcal/mol (AChE) were recorded using molecular docking software. Compound V exhibited strong free radical scavenging and anticholinesterase potentials suggesting that it can be effectively used to treat oxidative stress and dementia in human.

Keywords: Anti-cholinesterase; Antioxidant; Bioactive compounds; Molecular docking; Ziziphus oxyphylla.

Figure 1

Chemical structures of compounds V-VII, isolated from roots of Z. oxyphylla.

Figure 2

Interaction of coumaric acid with AChE and BChE crystal structures (Surface and ball and stick representation of the docking pose in the active site of AChE and BChE (1 ACL, 4BOP), showing the highly ranked pose for the active compound, p-coumaric acid, shown as green. The inhibitor predicted to bind in the active site in the space close to the water molecule. Residue, in stick representation, that forming the active site of the enzyme are labelled). (a). 2D diagram of ligand and AChE protein residues in contact. (b). Docked ligand in the active binding pocket of AChE (c). 2D diagram of ligand and BChE protein residues in contact. (d). Docked ligand in the active binding pocket of BChE.