title: Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents.
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.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Kincaid
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: Nir
authors.initials: N
authors.lastname: London
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Kittikhun
authors.initials: K
authors.lastname: Wangkanont
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Wesener
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Marcus
authors.affiliation: Photon Sciences Directorate, Brookhaven National Laboratories , Upton, New York 11973, United States.
authors.forename: Annie
authors.initials: A
authors.lastname: Héroux
authors.affiliation: Ontario Institute of Cancer Research and Faculty of Pharmacy, University of Toronto , Toronto, Canada.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Nedyalkova
authors.affiliation: Department of Pathobiological Sciences, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Adel M
authors.initials: AM
authors.lastname: Talaat
authors.affiliation: Department of Bacteriology, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Katrina T
authors.initials: KT
authors.lastname: Forest
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.|Ontario Institute of Cancer Research and Faculty of Pharmacy, University of Toronto , Toronto, Canada.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.|Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kiessling
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D019751:Intramolecular Transferases / Q000737:chemistry* / Q000235:genetics; D008024:Ligands; D008954:Models, Biological; D062105:Molecular Docking Simulation; D015394:Molecular Structure
chemical_list: D000900:Anti-Bacterial Agents; D008024:Ligands; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase