Systems-wide analysis of <i>A. fumigatus</i> using kinetic modeling of metabolic pathways to identify putative drug targets

Aspergillosis is a major causative factor for morbidity in those with impaired immune systems, often caused by <i>Aspergillus fumigatus</i>. The diagnosis and treatment are difficult due to the diversity of individuals and risk factors and still pose a challenge for medical professionals. To understand the pathogenicity of any organism, it is critical to identify the significant metabolic pathways that are involved. Our work focused on developing kinetic models of critical pathways crucial for the survival of <i>A. fumigatus</i> using COPASI. While focusing on the folate biosynthesis, ergosterol biosynthesis and glycolytic pathway; sensitivity, time-course and steady-state analysis were performed to find the proteins/enzymes that are essential in the pathway and can be considered as potential drug targets. For further analysis of the interaction of drug targets identified, a protein–protein interaction (PPI) network was built, and hub nodes were identified using the Cytohubba package from Cytoscape. Based on the findings, dihydropteroate-synthase, dihydrofolate-reductase, 4-amino-4-deoxychorismate synthase, HMG-CoA-reductase, PG-isomerase and hexokinase could act as potential drug targets. Further, molecular docking and MM-GBSA analysis were performed with ligands chosen from DrugBank, and PubChem, and validated by experimental evidence and existing literature based on results from kinetic modeling and PPI network analysis. Based on docking scores and MM-GBSA results, molecular simulations were carried out for 1AJ2-dapsone, 1DIS-sulfamethazine, 1T02-lovastatin and 70YL-3-bromopyruvic acid complexes, which validated our findings. Our study provides a deeper insight into the mechanisms of <i>A. fumigatus</i>’s metabolism to reveal dapsone, sulfamethazine, lovastatin and 3-bromopyruvic acid as potential drugs for the treatment of Aspergillosis. Communicated by Ramaswamy H. Sarma曲霉病（Aspergillosis）是免疫功能受损人群发病的主要诱因，其病原体多为烟曲霉（Aspergillus fumigatus）。由于患者个体特征与危险因素存在多样性，该病的诊断与治疗难度较高，至今仍是临床医务工作者面临的严峻挑战。要阐明生物体的致病机制，明确其核心参与的代谢通路至关重要。本研究借助COPASI软件，构建了烟曲霉（A. fumigatus）生存必需的核心代谢通路动力学模型。研究聚焦叶酸生物合成、麦角固醇生物合成及糖酵解通路，通过敏感性分析、时间进程分析与稳态分析，筛选出通路中不可或缺的蛋白质/酶类，作为潜在药物靶点。为深入分析筛选得到的药物靶点间的相互作用，本研究构建了蛋白质-蛋白质相互作用（PPI）网络，并借助Cytoscape的Cytohubba插件识别核心节点。基于分析结果，二氢蝶酸合酶、二氢叶酸还原酶、4-氨基-4-脱氧分支酸合酶、HMG-CoA还原酶、PG异构酶及己糖激酶可作为潜在药物靶点。基于动力学建模与PPI网络分析的结果，本研究从DrugBank与PubChem数据库中遴选配体，开展分子对接与MM-GBSA分析，并通过实验证据与现有文献对结果进行验证。结合对接评分与MM-GBSA分析结果，本研究针对1AJ2-氨苯砜、1DIS-磺胺二甲嘧啶、1T02-洛伐他汀及70YL-3-溴丙酮酸复合物开展分子动力学模拟，进一步验证了研究结论。本研究深入阐明了烟曲霉的代谢机制，揭示氨苯砜、磺胺二甲嘧啶、洛伐他汀及3-溴丙酮酸可作为治疗曲霉病的潜在药物。由Ramaswamy H. Sarma转交