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

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.

TCMBank: bridges between the largest herbal medicines, chemical ingredients, target proteins, and associated diseases with intelligence text mining

“…Wang et al 87 applied CNN, network pharmacology, and MD simulations to obtain multiple-target drugs caffeoyl malic acid for atopic dermatitis. Zhang et al 88 constructed a QSAR model to screen TCM for anti-atopic dermatitis drugs using NB and recursive partitioning (RP) methods. Zhu et al 89 used molecular docking and random forest methods to build a QSAR model to screen 30 potential inhibitors of TLR4 for the treatment of Mycoplasma pneumoniae.…”

Natural product-based pharmacological studies for neurological disorders

“…AD and dementia are diseases of the elderly society and have become one of the major concerns in health management because of the unattainability of medicinal treatment in this area ( Liu et al, 2022 ). Pathophysiologically, AD is an accelerating neuro-degenerative disease, resulting in the change of behavioral patterns and cognitive defects, and is the recurring source of dementia in approximately 80% of the diseased population, expected to increase three times by 2050 ( Zhang et al, 2021a ). Various target receptors are responsible for this condition, including the scarcity of important neurotransmitter acetylcholine (ACh), accumulation of β-amyloid proteins, largely phosphorylated tau plaques, and variation in glutamate pathways, neuro-inflammation, and different pathways, which participate in the pathological mechanism of the particular diseased condition ( Thomford et al, 2018 ).…”

Molecular mechanism of ovarian toxicity of <italic><bold>Tripterygium wilfordii</bold></italic> Hook.F.<bold>:</bold> a study based on network pharmacology and molecular docking

“…胞成熟过程中颗粒细胞的正常功能 至关重要 [27] 。PI3K/AKT/mTOR 信 号通路是重要的细胞内信号转导通 路，参与卵母细胞的生长发育、闭锁 和颗粒细胞的增殖分化，而卵泡过 度凋亡可能导致卵巢过早衰老 [28] 。 AKT1是一种已知致癌基因，可以调 节新陈代谢、增殖、细胞存活和生长 等诸多过程。在哺乳动物卵巢中， AKT1可调控卵泡和卵母细胞发育， 并在整个卵泡形成过程中调控颗粒 细胞凋亡，因此AKT1失调与多种 卵巢疾病相关 [29] 。可见 mTOR 和 AKT1 在维持正常卵巢功能中具有 重要作用。STAT3是 STAT 家族成 员，在细胞增殖、分化、凋亡等过程 中起着关键作用。STAT3在小鼠原 代卵泡、原代卵泡和次生卵泡中均 有高表达，并在发育过程中出现一 定的表达变化 [30] 。EGFR作为上游 基因，通过 PI3K/AKT 信号通路在调 节雌性生殖中起关键作用。EGFR 不仅能影响卵巢激素的分泌，还能 调节卵泡的生长发育 [31] 。肿瘤学研 究表明，KRAS和CDH1基因在卵巢疾 病中起重要作用 [32][33] 。因此，基于 上述基因在卵巢疾病中的重要作 用，本研究的生物信息学分析结果 是可靠的。 图 3 雷公藤卵巢毒性靶点的基因本体(GO)富集分析结果排序前20条目 蛋白的结合能力越强 [13] 。毒性化合物与毒性靶…”