Alam Aftab, Alqarni Mohammed H, Alotaibi Bader S, Khan Farhan R, Alam Md Shamsher, Aba Alkhayl Faris F, Alhafi Ali A, Almutairi Turki M, Alharbi Zeyad M, Alshehri Faez Falah
Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
Department of Clinical Laboratory Science, College of Applied Medical Sciences, Al-Quwayiyah, Shaqra University, Riyadh, Saudi Arabia.
J Biomol Struct Dyn. 2024 Sep 18:1-18. doi: 10.1080/07391102.2024.2404145.
Tuberculosis (TB) is a global health challenge; therefore, there is an urgent requirement to develop a novel and more effective anti-TB therapeutic. This study targeted the isocitrate lyase (ICL) protein due to its pivotal role in the pathogenicity of (Mtb). Virtual screening of 8752 bioactive compounds used an ML-based QSAR model and molecular docking. ADMET testing was performed on the top three hits to identify the compound most closely mimicking a drug molecule. The top hits, and , showed high binding affinity towards ICL with -7.3 and -7 kcal/mol, comparable to the control. These molecules also showed strong binding with the residue Asp108, which plays a vital role in ICL activity. Molecular dynamics simulations showed stability for and , comparable to the control compound used in this study. It was found that bound to the protein maintained the RMSD constant and consistent at 0.3 nm for a complete 100 ns simulation. showed a comparable RMSD trend to the control. Both and showed high RMSF for critical residue Asp108. Further, PCA and FEL confirmed the formation of a stable complex. MM/GBSA estimations of binding free energy indicated that compounds had an elevated level of stability (Δ = -28.11 kcal/mol) and (Δ = -21.05 kcal/mol). This study suggests that compounds and can potentially affect the activity of ICL, leading to its inactivation and ultimately preventing the progression of tuberculosis.Communicated by Ramaswamy H. Sarma.
结核病（TB）是一项全球性的健康挑战；因此，迫切需要开发一种新型且更有效的抗结核治疗方法。由于异柠檬酸裂解酶（ICL）蛋白在结核分枝杆菌（Mtb）的致病性中起关键作用，本研究将其作为靶点。使用基于机器学习的定量构效关系（QSAR）模型和分子对接对8752种生物活性化合物进行虚拟筛选。对排名前三的命中化合物进行了药物代谢及毒性（ADMET）测试，以确定最接近药物分子的化合物。排名靠前的命中化合物与 ，对ICL表现出高结合亲和力，分别为 -7.3和 -7千卡/摩尔，与对照相当。这些分子还与在ICL活性中起关键作用的残基Asp108表现出强结合。分子动力学模拟显示与 ，与本研究中使用的对照化合物相当的稳定性。发现在完整的100纳秒模拟中，与蛋白质结合的 保持均方根偏差（RMSD）恒定且一致，为0.3纳米。 显示出与对照相当的RMSD趋势。 与 对关键残基Asp108均表现出高均方根波动（RMSF）。此外，主成分分析（PCA）和自由能景观（FEL）证实形成了稳定的复合物。结合自由能的MM/GBSA估计表明，化合物 具有更高的稳定性水平（Δ = -28.11千卡/摩尔）和 （Δ = -21.05千卡/摩尔）。本研究表明，化合物 和 可能会影响ICL的活性，导致其失活并最终阻止结核病的进展。由拉马斯瓦米·H·萨尔马传达。
