Probing binding requirements of NAD kinase with modified substrate (NAD) analogues.
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.
Bonnac
Laurent
L
Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
Chen
Liqiang
L
Pathak
Rashmi
R
Gao
Guangyao
G
Ming
Qian
Q
Bennett
Eric
E
Felczak
Krzysztof
K
Kullberg
Martin
M
Patterson
Steven E
SE
Mazzola
Francesca
F
Magni
Giulio
G
Pankiewicz
Krzysztof W
KW
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
D001549:Benzamides; D004791:Enzyme Inhibitors; D009243:NAD; D017853:Phosphotransferases (Alcohol Group Acceptor); C021844:NAD kinase; D008274:Magnesium