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ACS Chem Biol. 2015 Oct 16;10(10):2209-18. doi: 10.1021/acschembio.5b00370. Epub 2015 Aug 17.

Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents.

Author information

1
Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
2
Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
3
Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
4
Department of Pathobiological Sciences, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
5
Photon Sciences Directorate, Brookhaven National Laboratories , Upton, New York 11973, United States.
6
Ontario Institute of Cancer Research and Faculty of Pharmacy, University of Toronto , Toronto, Canada.
7
Department of Bacteriology, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.

Abstract

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.

PMID:
26214585
PMCID:
PMC4669066
DOI:
10.1021/acschembio.5b00370
[Indexed for MEDLINE]
Free PMC Article

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