Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay
To address the surge in <i>Aspergillus fumigatus</i> infections among immunosuppressed patients and azole resistance, this study focused on developing novel inhibitors targeting dihydroorotate dehydrogenase (AfDHODH), a key enzyme in fungal pyrimidine synthesis. The three-dimensional str...
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MDPI AG
2025-06-01
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| author | Kaige Li Wei Xia John Z. H. Zhang |
| author_facet | Kaige Li Wei Xia John Z. H. Zhang |
| author_sort | Kaige Li |
| collection | DOAJ |
| description | To address the surge in <i>Aspergillus fumigatus</i> infections among immunosuppressed patients and azole resistance, this study focused on developing novel inhibitors targeting dihydroorotate dehydrogenase (AfDHODH), a key enzyme in fungal pyrimidine synthesis. The three-dimensional structure of AfDHODH was constructed via homology modeling. Molecular docking, dynamics simulations, and binding free energy calculations systematically elucidated the mechanisms of existing inhibitors. Virtual screening against the ZINC20 and ChEMBL databases yielded 13 candidates, with two micromolar inhibitors (IC<sub>50</sub> < 100 μM) identified through in vitro assays. These inhibitors exhibited novel scaffold structures that were distinct from known DHODH inhibitors. The results validate the feasibility of homology modeling-guided antifungal discovery and these findings provide critical insights for the development of new antifungal agents. |
| format | Article |
| id | doaj-art-0c72e23b0c3d436c98daa89b67c2542f |
| institution | Matheson Library |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-0c72e23b0c3d436c98daa89b67c2542f2025-06-25T14:13:41ZengMDPI AGMolecules1420-30492025-06-013012260710.3390/molecules30122607Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity AssayKaige Li0Wei Xia1John Z. H. Zhang2Shanghai Engineering Research Center of Molecular Therapeutics and New Drug, Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaNYU-ECNU Center for Computational Chemistry and Shanghai Frontiers Science Center of AI and DL, New York University Shanghai, Shanghai 200126, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug, Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, ChinaTo address the surge in <i>Aspergillus fumigatus</i> infections among immunosuppressed patients and azole resistance, this study focused on developing novel inhibitors targeting dihydroorotate dehydrogenase (AfDHODH), a key enzyme in fungal pyrimidine synthesis. The three-dimensional structure of AfDHODH was constructed via homology modeling. Molecular docking, dynamics simulations, and binding free energy calculations systematically elucidated the mechanisms of existing inhibitors. Virtual screening against the ZINC20 and ChEMBL databases yielded 13 candidates, with two micromolar inhibitors (IC<sub>50</sub> < 100 μM) identified through in vitro assays. These inhibitors exhibited novel scaffold structures that were distinct from known DHODH inhibitors. The results validate the feasibility of homology modeling-guided antifungal discovery and these findings provide critical insights for the development of new antifungal agents.https://www.mdpi.com/1420-3049/30/12/2607AfDHODHsmall molecule inhibitorsvirtual screeningcomputer-aided drug designbinding free energy |
| spellingShingle | Kaige Li Wei Xia John Z. H. Zhang Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay Molecules AfDHODH small molecule inhibitors virtual screening computer-aided drug design binding free energy |
| title | Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay |
| title_full | Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay |
| title_fullStr | Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay |
| title_full_unstemmed | Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay |
| title_short | Discovery of Novel Inhibitors of <i>Aspergillus fumigatus</i> DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay |
| title_sort | discovery of novel inhibitors of i aspergillus fumigatus i dhodh via virtual screening md simulation and in vitro activity assay |
| topic | AfDHODH small molecule inhibitors virtual screening computer-aided drug design binding free energy |
| url | https://www.mdpi.com/1420-3049/30/12/2607 |
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