Khan Sajjad Ahmed, Rather Muzafar Ahmad, Jia Ziyi, Qadir Syed Mehmood, Khan Muhammad Umer, Ejaz Hasan, Alruwaili Muharib, Baughn Anthony D, Thomas Shier W, Ahmad Muhammad Sheeraz
University Institute of Biochemistry and Biotechnology, PMAS-Arid Agriculture University Rawalpindi, Rawalpindi 46300, Pakistan; Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; National Reference Laboratory for Tuberculosis, National TB Control Program, Islamabad 44000, Pakistan.
Department of Microbiology & Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Bioorg Chem. 2025 Aug;163:108668. doi: 10.1016/j.bioorg.2025.108668. Epub 2025 Jun 3.
The persistent global health challenges posed by Mycobacterium tuberculosis (Mtb) underscore the urgent need to identify novel antitubercular agents from natural origin. The objective of this research is to assess the antitubercular potential of phytocompounds from Datura innoxia against Mtb through in vitro and in silico methods. Eleven natural compounds were screened for antitubercular activity. The molecular docking and pharmacokinetic properties of the lead compounds were assessed against 10 protein targets. Additionally, density functional theory (DFT), and molecular dynamics (MD) simulation were conducted to further evaluate the compound's properties. C-1 (trans-3-indoleacrylic acid) exhibited the strongest antitubercular activity against Mtb H37Ra strain, with a minimal inhibitory concentration (MIC) of 3.12 μg/mL and minimal bactericidal concentration (MBC) of 12.5 μg/mL. C-2 (indole-3-lactic acid) demonstrated the best binding affinity (9.571 kcal/mol), followed by C-1 (-7.467 kcal/mol), particularly with protein PknB (PDB ID: 5U94). In silico ADMET and DFT analyses indicated favorable pharmacokinetics of C-2, and MD simulations further confirmed its stability. C-1 (trans-3-indoleacrylic acid) exhibited the best in vitro activity, while C-2 (indole-3-lactic acid) showed the strongest in silico results. Both candidates are promising agents due to their potent efficacy and favorable stability profiles, and can be used alone or in combination with other antitubercular agents.
结核分枝杆菌（Mtb）给全球健康带来的持续挑战凸显了从天然来源鉴定新型抗结核药物的迫切需求。本研究的目的是通过体外和计算机模拟方法评估白花曼陀罗植物化合物对Mtb的抗结核潜力。筛选了11种天然化合物的抗结核活性。针对10个蛋白质靶点评估了先导化合物的分子对接和药代动力学性质。此外，还进行了密度泛函理论（DFT）和分子动力学（MD）模拟以进一步评估该化合物的性质。C-1（反式-3-吲哚丙烯酸）对Mtb H37Ra菌株表现出最强的抗结核活性，最低抑菌浓度（MIC）为3.12μg/mL，最低杀菌浓度（MBC）为12.5μg/mL。C-2（吲哚-3-乳酸）表现出最佳的结合亲和力（9.571千卡/摩尔），其次是C-1（-7.467千卡/摩尔），特别是与蛋白质PknB（PDB ID：5U94）。计算机模拟的ADMET和DFT分析表明C-2具有良好的药代动力学性质，MD模拟进一步证实了其稳定性。C-1（反式-3-吲哚丙烯酸）表现出最佳的体外活性，而C-2（吲哚-3-乳酸）显示出最强的计算机模拟结果。这两种候选物因其强大的功效和良好的稳定性而都是有前景的药物，可单独使用或与其他抗结核药物联合使用。
