Structural highlights
FunctionPublication Abstract from PubMedGalactofuranose (Galf) is present in glycans critical for 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 as antimicrobial leads and 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, non-carbohydrate 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 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. Virtual screening for UDP-galactopyranose mutase ligands identifies a new class of antimycobacterial agents.,Kincaid VA, London N, Wangkanont K, Wesener DA, Marcus SA, Heroux A, Nedyalkova L, Talaat AM, Forest KT, Shoichet BK, Kiessling LL ACS Chem Biol. 2015 Jul 27. PMID:26214585[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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