Identification of Multi-Target Anti-AD Chemical Constituents From Traditional Chinese Medicine Formulae by Integrating Virtual Screening and In Vitro Validation.

Baoyue Zhang,Pengfei Guo,Zhe Wang,Ailin Liu,Guanhua Du,Jun Zhao

doi:10.3389/fphar.2021.709607

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that seriously threatens the health of the elderly. At present, no drugs have been proven to cure or delay the progression of the disease. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach provides an innovative and promising idea in search for new drugs against AD. In order to find potential multi-target anti-AD drugs from traditional Chinese medicine (TCM) formulae, a compound database derived from anti-AD Chinese herbal formulae was constructed and predicted by the anti-AD multi-target drug prediction platform established in our laboratory. By analyzing the results of virtual screening, 226 chemical constituents with 3 or more potential AD-related targets were collected, from which 16 compounds that were predicted to combat AD through various mechanisms were chosen for biological validation. Several cell models were established to validate the anti-AD effects of these compounds, including KCl, Aβ, okadaic acid (OA), SNP and H2O2 induced SH-SY5Y cell model and LPS induced BV2 microglia model. The experimental results showed that 12 compounds including Nonivamide, Bavachromene and 3,4-Dimethoxycinnamic acid could protect model cells from AD-related damages and showed potential anti-AD activity. Furthermore, the potential targets of Nonivamide were investigated by molecular docking study and analysis with CDOCKER revealed the possible binding mode of Nonivamide with its predicted targets. In summary, 12 potential multi-target anti-AD compounds have been found from anti-AD TCM formulae by comprehensive application of computational prediction, molecular docking method and biological validation, which laid a theoretical and experimental foundation for in-depth study, also providing important information and new research ideas for the discovery of anti-AD compounds from traditional Chinese medicine.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease with unclear etiology and pathogenesis (Lane et al, 2018), which is usually characterized by progressive loss of short-term memory, damage of language function, accompanied by spatial discrimination impairment, agnosia, and even personality and behavioral changes with the aggravation of disease (Albert et al, 2011)
According to the preliminary studies, the pathogenesis of AD was mainly related to amyloid β-protein fragment 1–42 (Aβ) plaques, but the therapeutic strategies aimed at reducing β-amyloid protein failed one after another (Loureiro et al, 2020; Knopman et al, 2021)
Based on the data mining of existing databases and literature investigation, we collected 125 traditional Chinese medicine formulae significantly related to AD, such as BushenYizhi decoction, Tongbi Yinao decoction, Xuefu Zhuyu decoction, etc., from which 102 herbs with a frequency greater than or equal to 3 were selected, such as Panax Ginseng C

Summary

INTRODUCTION

Alzheimer’s disease (AD) is a neurodegenerative disease with unclear etiology and pathogenesis (Lane et al, 2018), which is usually characterized by progressive loss of short-term memory, damage of language function, accompanied by spatial discrimination impairment, agnosia, and even personality and behavioral changes with the aggravation of disease (Albert et al, 2011). Emerging evidence has confirmed that the mechanisms of TCM treatment for AD include improving Aβ plaques, abnormal phosphorylation of tau protein, neuroinflammation, and oxidative stress (Tobore, 2019), as well as the improvement of microglia activity (Xia et al, 2017), regulation of heat shock protein pathway, MAPK pathway, mitochondrial membrane potential and release of cytochrome C, and so on (Zong et al, 2016; Dinda et al, 2019). Based on TCM formulae application database, natural products database and anti-AD multi-target prediction platform established in our laboratory, this study predicted the AD-related target-compound interaction in order to find the potential multi-target constituents from TCM formulae for the prevention and treatment of AD. This study provides important information for the discovery of new drugs in traditional Chinese medicine formulae for AD treatment

MATERIALS AND METHODS

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT