Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents
| Autor: | Kincaid, Virginia A, London, Nir, Wangkanont, Kittikhun, Wesener, Darryl A, Marcus, Sarah A, Héroux, Annie, Nedyalkova, Lyudmila, Talaat, Adel M, Forest, Katrina T, Shoichet, Brian K, Kiessling, Laura L |
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| Rok vydání: | 2015 |
| Předmět: |
Crystallography
Molecular Structure Organic Chemistry Biological Sciences Ligands Biological Preclinical Anti-Bacterial Agents Molecular Docking Simulation Rare Diseases Good Health and Well Being Models 5.1 Pharmaceuticals Chemical Sciences X-Ray Drug Evaluation Development of treatments and therapeutic interventions Intramolecular Transferases |
| Zdroj: | ACS chemical biology, vol 10, iss 10 |
| Popis: | Galactofuranose (Galf) is present in glycans critical for the virulence and viability of several pathogenic microbes, including Mycobacterium tuberculosis, yet the monosaccharide is absent from mammalian glycans. Uridine 5'-diphosphate-galactopyranose mutase (UGM) catalyzes the formation of UDP-Galf, which is required to produce Galf-containing glycoconjugates. Inhibitors of UGM have therefore been sought, both as antimicrobial leads and as tools to delineate the roles of Galf in cells. Obtaining cell permeable UGM probes by either design or high throughput screens has been difficult, as has elucidating how UGM binds small molecule, noncarbohydrate inhibitors. To address these issues, we employed structure-based virtual screening to uncover new inhibitor chemotypes, including a triazolothiadiazine series. These compounds are among the most potent antimycobacterial UGM inhibitors described. They also facilitated determination of a UGM-small molecule inhibitor structure, which can guide optimization. A comparison of results from the computational screen and a high-throughput fluorescence polarization (FP) screen indicated that the scaffold hits from the former had been evaluated in the FP screen but missed. By focusing on promising compounds, the virtual screen rescued false negatives, providing a blueprint for generating new UGM probes and therapeutic leads. |
| Databáze: | OpenAIRE |
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