title: Herpes simplex virus ribonucleotide reductase subunit association inhibitors: the effect and conformation of beta-alkylated aspartic acid derivatives.
abstract: 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.
authors.affiliation: Bio-Méga/Boehringer Ingelheim Research Inc., Layal, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Moss
authors.forename: R
authors.initials: R
authors.lastname: Déziel
authors.forename: J M
authors.initials: JM
authors.lastname: Ferland
authors.forename: S
authors.initials: S
authors.lastname: Goulet
authors.forename: P J
authors.initials: PJ
authors.lastname: Jones
authors.forename: S F
authors.initials: SF
authors.lastname: Leonard
authors.forename: T P
authors.initials: TP
authors.lastname: Pitner
authors.forename: R
authors.initials: R
authors.lastname: Plante
mesh_terms: 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*
chemical_list: D046911:Macromolecular Substances; D014764:Viral Proteins; D001224:Aspartic Acid; D012264:Ribonucleotide Reductases