Drug-resistant tuberculosis (TB) infections are on the rise and anti-tuberculosis drugs that inhibit Mycobacterium tuberculosis (M. tuberculosis) through a new novel mechanism could be an important component of evolving TB therapy. Pantothenate kinase (PanK) and CTP synthetase (PyrG) are both essential for de novo pyrimidine biosynthesis. Given the extensive knowledge base on de novo pyrimidine biosynthesis inhibition of M. tuberculosis growth and survival, these enzymes present an interesting opportunity for anti-mycobacterial drug discovery. A recent experimental study shows that CDD-823953 and GSK-735826A act as dual PanK and PyrG inhibitors, respectively. However, the molecular mechanisms of their selective inhibition remain elusive. Herein, density functional theory (DFT) calculation was applied to unveil the molecular and reactivity properties of two lead compounds targeting these enzymes in a shot. Molecular dynamics simulations were then employed to investigate the inhibitory mechanism as well as selectivity impact of these potential inhibitors for their enzymes. Computational modeling of the ligands and the enzyme–ligand systems reveal that CDD-823953 and GSK-735826A lead compounds can potentially inhibit both PanK and PyrG thereby creating a pathway via the use of double target approach in tuberculosis treatment.

中文翻译：

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结核分枝杆菌药物发现的双重靶向方法：来自 DFT 计算和分子动力学模拟的见解

耐药性结核病 (TB) 感染呈上升趋势，而通过新机制抑制结核分枝杆菌 (M.tuberculosis) 的抗结核药物可能成为不断发展的结核病治疗的重要组成部分。泛酸激酶 (PanK) 和 CTP 合成酶 (PyrG) 都是嘧啶从头生物合成所必需的。鉴于从头嘧啶生物合成抑制结核分枝杆菌生长和存活的广泛知识基础，这些酶为抗分枝杆菌药物的发现提供了一个有趣的机会。最近的一项实验研究表明，CDD-823953 和 GSK-735826A 分别作为 PanK 和 PyrG 双重抑制剂。然而，它们选择性抑制的分子机制仍然难以捉摸。在此处，应用密度泛函理论 (DFT) 计算来揭示两种针对这些酶的先导化合物的分子和反应特性。然后采用分子动力学模拟来研究这些潜在抑制剂对其酶的抑制机制以及选择性影响。配体和酶-配体系统的计算模型表明，CDD-823953 和 GSK-735826A 先导化合物可以潜在地抑制 PanK 和 PyrG，从而通过在结核病治疗中使用双靶点方法创建途径。