title: Triazole-linked inhibitors of inosine monophosphate dehydrogenase from human and Mycobacterium tuberculosis.
abstract: The modular nature of nicotinamide adenine dinucleotide (NAD)-mimicking inosine monophsophate dehydrogenase (IMPDH) inhibitors has prompted us to investigate novel mycophenolic adenine dinucleotides (MAD) in which 1,2,3-triazole linkers were incorporated as isosteric replacements of the pyrophosphate linker. Synthesis and evaluation of these inhibitors led to identification of low nanomolar inhibitors of human IMPDH and more importantly the first potent inhibitor of IMPDH from Mycobacterium tuberculosis (mtIMPDH). Computational studies of these IMPDH enzymes helped rationalize the observed structure-activity relationships. Additionally, the first cloning, expression, purification and characterization of mtIMPDH is reported.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware Street SE, Minneapolis, Minnesota 55455, USA. chenx462@umn.edu
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.forename: Yanli
authors.initials: Y
authors.lastname: Xu
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Felczak
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D007700:Kinetics; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000227:Adenine Nucleotides; D000995:Antitubercular Agents; D011994:Recombinant Proteins; D014230:Triazoles; C110804:mycophenolic adenine dinucleotide; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid