title: Synthesis of natural product-inspired inhibitors of Mycobacterium tuberculosis mycothiol-associated enzymes: the first inhibitors of GlcNAc-Ins deacetylase.
abstract: Synthesis and evaluation of a chemical library of inhibitors of the mycothiol biosynthesis enzyme GlcNAc-Ins deacetylase (MshB) and the mycothiol-dependent detoxification enzyme mycothiol- S-conjugate amidase (MCA) from Mycobacterium tuberculosis are reported. The library was biased to include structural features of a group of natural products previously shown to competitively inhibit MCA. Molecular docking studies that reproducibly placed the inhibitors in the active site of the enzyme MshB reveal the mode of binding and are consistent with observed biological activity.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Belhu B
authors.initials: BB
authors.lastname: Metaferia
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Fetterolf
authors.forename: Syed
authors.initials: S
authors.lastname: Shazad-Ul-Hussan
authors.forename: Matthew
authors.initials: M
authors.lastname: Moravec
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Smith
authors.forename: Satyajit
authors.initials: S
authors.lastname: Ray
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Gutierrez-Lugo
authors.forename: Carole A
authors.initials: CA
authors.lastname: Bewley
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D003545:Cysteine / Q000378:metabolism*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry; D006020:Glycopeptides / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism*; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry; D013865:Thioglycosides / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D005663:Furans; D006020:Glycopeptides; D007555:Isoxazoles; D010078:Oxazines; D010080:Oxazoles; D011714:Pyrans; D013449:Sulfonamides; D013865:Thioglycosides; C089265:mycothiol; D007294:Inositol; D000581:Amidohydrolases; C417275:N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase; C413523:mycothiol S-conjugate amidase; D003545:Cysteine