Herpes simplex virus ribonucleotide reductase subunit association inhibitors: the effect and conformation of beta-alkylated aspartic acid derivatives.
Incorporating beta-alkylated aspartic acid derivatives into herpes simplex virus ribonucleotide reductase subunit association inhibitors can improve inhibitor potency up to 50 times over the corresponding inhibitors containing an unsubstituted aspartic acid. A combination of NMR studies, conformational analysis, and molecular mechanics calculations suggests that the beta-alkyl group improves inhibitor potency by favoring the bioactive conformation of the critical aspartic acid carboxyl group. Further support for this hypothesis is provided by a potent conformationally restricted aspartic acid derivative in which the carboxyl group is locked in the putative bioactive conformation.
Moss
N
N
Bio-Méga/Boehringer Ingelheim Research Inc., Layal, Quebec, Canada.
Déziel
R
R
Ferland
J M
JM
Goulet
S
S
Jones
P J
PJ
Leonard
S F
SF
Pitner
T P
TP
Plante
R
R
D000478:Alkylation; D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D046911:Macromolecular Substances; D014764:Viral Proteins; D001224:Aspartic Acid; D012264:Ribonucleotide Reductases