A network pharmacology-based approach to understand the mechanism of action of anti-mycobacterial activity of Acacia nilotica: a modelling and experimental study

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Madhumitha Suresh, Kadambari Vijay Sai, Kartik Mitra, Radhika Ravindran, Mukesh Doble
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Abstract

The rapid rise in drug-resistant tuberculosis poses a serious threat to public health and demands the discovery of new anti-mycobacterial agents. Medicinal plants are a proven potential source of bioactive compounds; however, identifying those responsible for the putative anti-mycobacterial action still remains a challenging task. In this study, we undertook a systematic network pharmacology approach to identify and evaluate anti-mycobacterial compounds from a traditional plant, Acacia nilotica, as a model system. The protein–protein interaction network revealed 17 key pathways in M. tuberculosis encompassing 40 unique druggable targets that are necessary for its growth and survival. The phytochemicals of A. nilotica were preferentially found to interfere with the cell division and cell wall biogenesis proteins, especially FtsZ and Mur. Notably, the compounds epigallocatechin, ellagic acid, chlorogenic acid, and D-pinitol were found to exhibit a potential polypharmacological effect against multiple proteins. Further, in vitro studies confirmed that the selected candidates, chlorogenic acid, and ellagic acid exhibited potent anti-mycobacterial activity (against M. smegmatis) with specific inhibition of purified M.tb FtsZ enzyme. Taken together, the present study demonstrates that network pharmacology combined with molecular docking can be utilized as an efficient approach to identify potential bioactive phytochemicals from natural products along with their mechanism of action. Hence, the compounds identified in this study can be potential lead candidates for developing novel anti-mycobacterial drugs, while the key proteins identified here can be potential drug targets.

Abstract Image

基于网络药理学的方法来理解金合欢抗霉菌活性的作用机制:一项建模和实验研究
耐药性结核病的迅速增加对公共健康构成了严重威胁,需要发现新的抗霉菌药物。药用植物是经证实的生物活性化合物的潜在来源;然而,确定哪些化合物具有可能的抗结核作用仍然是一项具有挑战性的任务。在这项研究中,我们采用了一种系统的网络药理学方法,以一种传统植物--黑相思为模型系统,来鉴定和评估抗霉菌化合物。蛋白-蛋白相互作用网络揭示了结核杆菌的 17 条关键通路,包括 40 个独特的可药物靶点,这些靶点是结核杆菌生长和存活所必需的。研究发现,A. nilotica 的植物化学物质优先干扰细胞分裂和细胞壁生物生成蛋白,尤其是 FtsZ 和 Mur。值得注意的是,研究发现表没食子儿茶素、鞣花酸、绿原酸和 D-松醇等化合物对多种蛋白质具有潜在的多药理作用。此外,体外研究证实,所选候选化合物、绿原酸和鞣花酸对纯化的 M.tb FtsZ 酶具有特异性抑制作用,表现出强大的抗霉菌活性(针对 M. smegmatis)。综上所述,本研究表明,网络药理学与分子对接相结合是一种有效的方法,可用于从天然产品中鉴定潜在的生物活性植物化学物质及其作用机制。因此,本研究发现的化合物可以成为开发新型抗霉菌药物的潜在候选先导化合物,而本研究发现的关键蛋白则可以成为潜在的药物靶标。
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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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