A novel strategy for exploring food originated anti-adipogenesis substances and mechanism by structural similarity evaluation, ADME prediction, network pharmacology and experimental validation
A novel strategy for exploring food originated anti-adipogenesis substances and mechanism by structural similarity evaluation, ADME prediction, network pharmacology and experimental validation
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通过结构相似性评估、ADME预测、网络药理学和实验验证探索食物源抗脂肪生成物质和机制的新策略
DOI：
10.1039/d1fo01124c
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发表时间：
2021
期刊：
影响因子：
6.1
通讯作者：
Qiu Zuo-cheng
中科院分区：
文献类型：
--
作者：
Zhang Feng-xiang;Tang Zi-ling;Qiu Zuo-cheng
由于天然产物（食品、草药等）中存在成百上千种可能的化合物，基于活性化合物筛选潜在的功能物质仍然是研究人员面临的挑战。本研究提出了结构相似性评价、ADME（吸收、分布、代谢、排泄）预测、网络药理学和实验验证相结合的综合策略（SANE策略），并应用于抗脂肪生成物质的探索。该策略分为四个部分：首先，通过相似性评价和ADME预测筛选出具有代表性的活性化合物。其次，利用分子生物学方法对目标化合物进行体外活性评价。第三，利用网络药理学探索潜在的靶点和通路。最后，用现代药理学方法确定其核心药理机制。结果筛选到化学结构与染料木黄酮相似的8-烯基染料木黄酮（8-prenylgenistein, 8PG），并提高了ADME性能。同时发现8PG在脂肪前3T3-L1细胞和原代人骨髓基质细胞（hBMSC）中具有显著的抗脂肪生成作用。通过化学染色、功能测定、Real - time PCR等方法，发现8PG在抑制脂肪细胞分化方面比染料木黄酮更有效。进一步预测其潜在的药理机制，并在信号通路阻断剂缺失/存在的情况下，通过免疫印迹和免疫荧光染色证实8PG对3T3-L1细胞和hBMSC中Wnt/β-catenin通路的激活有显著作用。本研究为在精确效应化合物的基础上探索更有效的化合物提供了新的思路。此外，还提供了一种抑制脂肪生成的潜在化合物（8PG）。
Screening potential functional substances based on active compounds is still a challenge faced by researchers since hundreds and thousands of possible compounds exist in natural products (food, herb, etc.). In this study, an integrated strategy by a combination of structural similarity evaluation, ADME (absorption, distribution, metabolism, excretion) prediction, network pharmacology and experimental validation (SANE strategy) was proposed and applied to explore anti-adipogenesis substances. This strategy was divided into four parts: first, potential compounds were screened based on representative active compounds by similarity evaluation and ADME prediction. Second, the activity of targeted compounds was evaluated in vitro based on the molecular biology method. Third, network pharmacology was used to explore potential targets and pathways. Last, the core pharmacological mechanism was confirmed by modern pharmacology methods. As a result, 8-prenylgenistein (8PG) was screened with chemical structure similarity with genistein and improved ADME propriety. Meanwhile, 8PG was found to present significant anti-adipogenesis effects in pre-adipocyte 3T3-L1 cells and primary human bone marrow stromal cells (hBMSC). Through using methods including: chemical staining, functional assays, and Real time PCR, 8PG was found to present more potency than genistein in suppressing the adipocyte differentiation. Further, the potential pharmacological mechanism was predicted, and significant effects of 8PG on activating the Wnt/β-catenin pathway in 3T3-L1 cells and hBMSC were confirmed by immunoblotting in the absence/presence of signaling pathway blocker and immunofluorescence staining. A new insight for exploring more potent compounds based on accurate effect compounds is provided in our work. Moreover, a potential compound (8PG), suppressing adipogenesis, was also supplied.