Chouhan Mandeep, Kumar Mukesh, Mishra Richa, Gupta Saurabh, Tiwari Prashant Kumar, Rustagi Sarvesh, Sharma Kuldeep, Singh Deependra Pratap, Kumar Sanjay
Biological and Bio-computational Lab, Department of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida UP, 201310, India.
Department of Biophysics, All India Institute of Medical Sciences, New Delhi, 110029, India.
Curr Drug Discov Technol. 2025 Jun 16. doi: 10.2174/0115701638364461250603050239.
The global burden of tuberculosis (TB) remains a major concern for society that is worsening day by day with the emergence of drug-resistant TB as well as risks associated with latent TB. Isocitrate lyase (ICL) has been shown as a potential target that plays a role in the la-tent/dormant stage of M. tuberculosis. Several inhibitors against ICL have been designed and tested, which have various side effects.
This study focuses on the phytochemicals from plant extracts, which have anti-tuber-cular properties. A total of 1413 phytochemicals were virtually screened against ICL to identify the promising therapeutic compounds. The top four lead phytochemicals were selected based on their binding energy and subjected to redocking and intermolecular interaction analysis. These results were further validated through 100 ns MD simulation to check the stability of these complexes. The find-ings of these complexes were compared to the reference compound VGX.
The top selected compound viz., Allantoin, Gallic acid, Citric acid, and 3,5-Dihydroxyben-zoic acid from virtual screening result displayed better docking score ranging from -8 kcal/mol to -7.2 kcal/mol than the reference compound VGX (-7.5 kcal/mol). Moreover, during the MD simula-tion analysis, gallic acid exhibited greater stability compared to all other compounds, including the reference compound.
Among selected phytochemicals, gallic acid exhibited highest stability and binding af-finity within the active site of ICL as compared to previously identified compounds, which suggests that it is as potential candidate against ICL. That can be used for further in vitro and in vivo studies to evaluate its effectiveness against TB.
结核病的全球负担仍然是社会主要关注的问题，随着耐药结核病的出现以及潜伏性结核病相关风险，这一问题日益恶化。异柠檬酸裂解酶（ICL）已被证明是在结核分枝杆菌潜伏/休眠阶段发挥作用的潜在靶点。已经设计并测试了几种针对ICL的抑制剂，这些抑制剂有各种副作用。
本研究聚焦于具有抗结核特性的植物提取物中的植物化学物质。对总共1413种植物化学物质进行了虚拟筛选以确定有前景的治疗化合物。根据结合能选择了前四种先导植物化学物质，并进行了重新对接和分子间相互作用分析。通过100纳秒的分子动力学模拟进一步验证这些结果，以检查这些复合物的稳定性。将这些复合物的研究结果与参考化合物VGX进行比较。
虚拟筛选结果中选出的顶级化合物，即尿囊素、没食子酸、柠檬酸和3,5 -二羟基苯甲酸，显示出比参考化合物VGX（-7.5千卡/摩尔）更好的对接分数，范围从-8千卡/摩尔到-7.2千卡/摩尔。此外，在分子动力学模拟分析期间，没食子酸与所有其他化合物（包括参考化合物）相比表现出更高的稳定性。
在选定的植物化学物质中，与先前鉴定的化合物相比，没食子酸在ICL活性位点内表现出最高的稳定性和结合亲和力，这表明它是针对ICL的潜在候选物。可用于进一步的体外和体内研究，以评估其对结核病的有效性。
