Systems-wide analysis of A. fumigatus 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 Aspergillus fumigatus. 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...

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Published in:	Journal of biomolecular structure & dynamics Vol. 42; no. 9; pp. 4379 - 4394
Main Authors:	Narad, Priyanka, Kulshrestha, Sudeepti, Chikara, Aryan, Gupta, Vinayak, Kakrania, Mahi, Saxena, Ritika, Gupta, Payal, Gupta, Lovely, Vijayaraghavan, Pooja, Sengupta, Abhishek
Format:	Journal Article
Language:	English
Published:	England Taylor & Francis 12-06-2024
Subjects:	Antifungal Agents - chemistry Antifungal Agents - metabolism Antifungal Agents - pharmacology Aspergillosis Aspergillus fumigatus - drug effects Aspergillus fumigatus - metabolism drug targets Fungal Proteins - chemistry Fungal Proteins - metabolism Humans kinetic modeling Kinetics Ligands MD simulation Metabolic Networks and Pathways metabolic pathways molecular docking Molecular Docking Simulation Molecular Dynamics Simulation Protein Interaction Maps protein-protein interaction network MD simulation molecular docking Aspergillosis drug targets protein-protein interaction network metabolic pathways kinetic modeling
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Summary:	Aspergillosis is a major causative factor for morbidity in those with impaired immune systems, often caused by Aspergillus fumigatus. 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 A. fumigatus 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 A. fumigatus's metabolism to reveal dapsone, sulfamethazine, lovastatin and 3-bromopyruvic acid as potential drugs for the treatment of Aspergillosis. Communicated by Ramaswamy H. Sarma
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0739-1102 1538-0254
DOI:	10.1080/07391102.2023.2223726