Deoxyribosyl analogues of methionyl and isoleucyl sulfamate adenylates as inhibitors of methionyl-tRNA and isoleucyl-tRNA synthetases.
2'-Deoxy, 3'-deoxy, and 2',3'-dideoxyribosyl surrogates of isoleucyl and methionyl sulfamate adenylates have been investigated to identify the pharmacophoric importance of the ribose group for the inhibition of Escherichia coli methionyl-tRNA (MRS) and isoleucyl-tRNA (IRS) synthetases. Molecular modeling of 2',3'-dideoxyribosyl Met-NHSO2-AMP (9) with the crystal structure of E. coli MRS revealed that the lack of the two hydroxyl groups on ribose was compensated by the formation of an extra hydrogen bond between the ring oxygen and His24, resulting in a small activity reduction.
Kim
Sung Eun
SE
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea.
Kim
Su Yeon
SY
Kim
Sunghoon
S
Kang
Taehee
T
Lee
Jeewoo
J
D001665:Binding Sites; D018360:Crystallography, X-Ray; D003838:Deoxyadenine Nucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006860:Hydrogen Bonding; D007533:Isoleucine-tRNA Ligase / Q000037:antagonists & inhibitors*; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D003838:Deoxyadenine Nucleotides; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D008718:Methionine-tRNA Ligase; D007533:Isoleucine-tRNA Ligase