title: Probing binding requirements of NAD kinase with modified substrate (NAD) analogues.
abstract: Synthesis of novel NAD(+) analogues that cannot be phosphorylated by NAD kinase is reported. In these analogues the C2' hydroxyl group of the adenosine moiety was replaced by fluorine in the ribo or arabino configuration (1 and 2, respectively) or was inverted into arabino configuration to give compound 3. Compounds 1 and 2 showed inhibition of human NAD kinase, whereas analogue 3 inhibited both the human and Mycobacterium tuberculosis NAD kinase. An uncharged benzamide adenine dinucleotide (BAD) was found to be the most potent competitive inhibitor (K(i)=90 microM) of the human enzyme reported so far.
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bonnac
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.forename: Rashmi
authors.initials: R
authors.lastname: Pathak
authors.forename: Guangyao
authors.initials: G
authors.lastname: Gao
authors.forename: Qian
authors.initials: Q
authors.lastname: Ming
authors.forename: Eric
authors.initials: E
authors.lastname: Bennett
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Felczak
authors.forename: Martin
authors.initials: M
authors.lastname: Kullberg
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Francesca
authors.initials: F
authors.lastname: Mazzola
authors.forename: Giulio
authors.initials: G
authors.lastname: Magni
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008274:Magnesium / Q000502:physiology; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D009243:NAD / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D009243:NAD; D017853:Phosphotransferases (Alcohol Group Acceptor); C021844:NAD kinase; D008274:Magnesium