Multi-Target Screening and Experimental Validation of Natural Products from Selaginella Plants against Alzheimer's Disease - PubMed (original) (raw)

Multi-Target Screening and Experimental Validation of Natural Products from Selaginella Plants against Alzheimer's Disease

Yin-Hua Deng et al. Front Pharmacol. 2017.

Abstract

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder which is considered to be the most common cause of dementia. It has a greater impact not only on the learning and memory disturbances but also on social and economy. Currently, there are mainly single-target drugs for AD treatment but the complexity and multiple etiologies of AD make them difficult to obtain desirable therapeutic effects. Therefore, the choice of multi-target drugs will be a potential effective strategy inAD treatment. To find multi-target active ingredients for AD treatment from Selaginella plants, we firstly explored the behaviors effects on AD mice of total extracts (TE) from Selaginella doederleinii on by Morris water maze test and found that TE has a remarkable improvement on learning and memory function for AD mice. And then, multi-target SAR models associated with AD-related proteins were built based on Random Forest (RF) and different descriptors to preliminarily screen potential active ingredients from Selaginella. Considering the prediction outputs and the quantity of existing compounds in our laboratory, 13 compounds were chosen to carry out the in vitro enzyme inhibitory experiments and 4 compounds with BACE1/MAO-B dual inhibitory activity were determined. Finally, the molecular docking was applied to verify the prediction results and enzyme inhibitory experiments. Based on these study and validation processes, we explored a new strategy to improve the efficiency of active ingredients screening based on trace amount of natural product and numbers of targets and found some multi-target compounds with biological activity for the development of novel drugs for AD treatment.

Keywords: Alzheimer; BACE1; MAO-B; Selaginella plants; multi-target SAR; multi-target screening.

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Figures

Figure 1

Figure 1

The spatial learning and memory ability of AD mice tested by Morris water maze [(A) NCG: normal control group; (B) MCG: model control group; (C) LDG: low dose group; (D) MDG: middle dose group; (E) HDG: high dose group]. This figure shows that TE has a remarkable improvement on learning and memory function for AD mice which mainly lies in the increased distance and this functional improvement is dose-dependent.

Figure 2

Figure 2

The chemical structures of 13 compounds that with inhibitory activity after multi-target SAR model prediction. Among them, eight are biflavones and the left five are selaginellins.

Figure 3

Figure 3

Verification of BACE1 and MAO-B Inhibition. This figure shows that all these four compounds (S-5, S-8, S-12, S-13) have good inhibitory activity in the in vitro validation test.

Figure 4

Figure 4

The docking results of S-8 bounding to BACE1 (left, PDB ID: 1TQF) and MAO-B (right, PDB ID: 2V5Z). The structure of S-8 is rendered green and the docking pocket surface was adjected to a suitable transparency.

Figure 5

Figure 5

The ligand interaction diagram of S-8 bounding to BACE1 (left, PDB ID: 1TQF) and MAO-B (right, PDB ID: 2V5Z). It is a 2D diagram of the original ligand and a schematic representation of the binding site residues, with the important interactions between ligand and binding site shown. For BACE1, the main binding force is the hydrogen bond force and pi-bond force with ASP (232A) and THR (231A); for MAO-B, the main binding force is the hydrogen bond force and pi-bond force with CYS (397A) and GLY (13A).

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