Ginger components as new leads for the design and development of novel multi-targeted anti-Alzheimer's drugs: a computational investigation

Abstract

Ginger (Zingiber officinale), despite being a common dietary adjunct that contributes to the taste and flavor of foods, is well known to contain a number of potentially bioactive phytochemicals having valuable medicinal properties. Although recent studies have emphasized their benefits in Alzheimer's disease, limited information is available on the possible mechanism by which it renders anti-Alzheimer activity. Therefore, the present study seeks to employ molecular docking studies to investigate the binding interactions between active ginger components and various anti-Alzheimer drug targets. Lamarckian genetic algorithm methodology was employed for docking of 12 ligands with 13 different target proteins using AutoDock 4.2 program. Docking protocol was validated by re-docking of all native co-crystallized ligands into their original binding cavities exhibiting a strong correlation coefficient value (r (2)=0.931) between experimentally reported and docking predicted activities. This value suggests that the approach could be a promising computational tool to aid optimization of lead compounds obtained from ginger. Analysis of binding energy, predicted inhibition constant, and hydrophobic/hydrophilic interactions of ligands with target receptors revealed acetylcholinesterase as most promising, while c-Jun N-terminal kinase was recognized as the least favorable anti-Alzheimer's drug target. Common structural requirements include hydrogen bond donor/acceptor area, hydrophobic domain, carbon spacer, and distal hydrophobic domain flanked by hydrogen bond donor/acceptor moieties. In addition, drug-likeness score and molecular properties responsible for a good pharmacokinetic profile were calculated by Osiris property explorer and Molinspiration online toolkit, respectively. None of the compounds violated Lipinski's rule of five, making them potentially promising drug candidates for the treatment of Alzheimer's disease.

Keywords: Alzheimer’s disease; ginger; molecular docking; structure–activity relationship; toxicity prediction.

Figure 1

Chemical structure of potential bioactive phytochemicals from Zingiber officinale. Abbreviation: Ac, acetyl.

Figure 2

The validation of accuracy and performance of AutoDock 4.2. Notes: The native and docked-ligands of AChE, blue and sky blue (A); TACE, pink and sky blue (B); BuChE, dark magenta and dark orange (C); NOS, light steel blue and purple (D); PDE-5, gold and pale green (E); NMDA, magenta and turquoise (F); COX-2, red and green (G); hCE-1, medium turquoise and khaki (H); COX-1, brown and fuchsia (I); GSK-3, blue and green (J); BACE-1, red and medium sea green (K); ACE, maroon and green (L); JNK, orange and sky blue (M) respectively. Abbreviations: AChE, acetylcholinesterase; TACE, TNF-α converting enzyme; BuChE, butyrylcholinesterase; NOS, nitric oxide synthase; PDE-5, phosphodiesterase-5; NMDA, N-methyl-D-aspartate; COX, cyclooxygenase; hCE-1, human carboxylesterase-1; GSK, glycogen-synthase-kinase-3β; BACE, β-site amyloid precursor protein cleaving enzyme; ACE, angiotensin-converting enzyme; JNK, c-Jun N-terminal kinase.

Figure 3

Plot between experimentally reported and docking predicted activities of native co-crystallized ligands of all 13 targets. Abbreviation: pK_i, negative logarithm of inhibition constant.

Figure 4

Plot between docked targets and negative logarithmic values of docking predicted K_i of ginger compounds. Abbreviations: AChE, acetylcholinesterase; TACE, TNF-α converting enzyme; BuChE, butyrylcholinesterase; NOS, nitric oxide synthase; PDE-5, phosphodiesterase-5; NMDA, N-methyl-D-aspartate; COX, cyclooxygenase; GSK, glycogen-synthase-kinase-3β; BACE, β-site amyloid precursor protein cleaving enzyme; ACE, angiotensin converting enzyme; JNK, c-Jun N-terminal kinase; hCE-1, human carboxylesterase-1; pK_i, negative logarithm of inhibition constant.

Figure 5

Suggested pharmacophore model of ginger compounds for eliciting anti-Alzheimer’s effects.

Figure 6

3D structures of proteins showing the binding sites (left), and main residues involved in the ligand–protein (right) interaction of compound 8 and AChE (A, B), compound 11 and TACE (C, D), compound 11 and BuChE (E, F), and compound 11 and NOS (G, H). Abbreviations: AChE, acetylcholinesterase; TACE, TNF-α converting enzyme; BuChE, butyrylcholinesterase; NOS, nitric oxide synthase.

Figure 7

An overview of the structural requirements of ginger compounds for their interaction with different target receptors associated with Alzheimer’s disease. Abbreviations: BuChE, butyrylcholinesterase; NOS, nitric oxide synthase; NMDA, N-methyl-D-aspartate; COX, cyclooxygenase; GSK, glycogen-synthase-kinase-3β; BACE, β-site amyloid precursor protein cleaving enzyme; ACE, angiotensin converting enzyme; JNK, c-Jun N-terminal kinase; Ac, acetyl.

Figure 8

The lowest energy configuration of docking result of compound 7 with binding pocket of acetylcholinesterase. Notes: The amino acids (blue) are shown as stick while compound 7 is presented as ball and stick style in olive green color. Dashed lines in green indicate H-bonds while π–π interaction is shown as orange line. Oxygens are in red and polar hydrogens in light gray color.

Figure 9

The docked compound 7 (yellow) and native Huperzine A (blue) in the binding pocket of human acetylcholinesterase.