Suresh Madhumitha, Sai Kadambari Vijay, Mitra Kartik, Ravindran Radhika, Doble Mukesh
Bioengineering and Drug Design Lab, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India.
Department of Biotechnology, Theevanam Additives Nutraceuts Pvt Ltd, IITM Bioincubator, IIT Madras, Chennai, 600036, India.
Mol Divers. 2025 Jun;29(3):2227-2242. doi: 10.1007/s11030-024-10985-8. Epub 2024 Sep 18.
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.
耐药结核病的迅速增加对公共卫生构成严重威胁，需要发现新的抗分枝杆菌药物。药用植物是已被证实的生物活性化合物潜在来源；然而，确定那些具有假定抗分枝杆菌作用的化合物仍然是一项具有挑战性的任务。在本研究中，我们采用了系统的网络药理学方法，以一种传统植物——阿拉伯胶树（Acacia nilotica）作为模型系统，来鉴定和评估抗分枝杆菌化合物。蛋白质-蛋白质相互作用网络揭示了结核分枝杆菌中的17条关键途径，这些途径包含40个独特的可成药靶点，这些靶点对其生长和存活至关重要。结果发现，阿拉伯胶树的植物化学物质优先干扰细胞分裂和细胞壁生物合成蛋白，特别是FtsZ和Mur。值得注意的是，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表现出潜在的多药效应。此外，体外研究证实，所选的绿原酸和鞣花酸候选物对耻垢分枝杆菌表现出强大的抗分枝杆菌活性，并对纯化的结核分枝杆菌FtsZ酶有特异性抑制作用。综上所述，本研究表明，网络药理学与分子对接相结合可作为一种有效的方法，从天然产物中鉴定潜在的生物活性植物化学物质及其作用机制。因此，本研究中鉴定出的化合物可能是开发新型抗分枝杆菌药物的潜在先导候选物，而这里鉴定出的关键蛋白质可能是潜在的药物靶点。
