title: Molecular modeling studies of aldose reductase inhibitors.
abstract: Molecular modeling studies using the AM1 quantum chemical method and a torsional fitting method have been conducted on a series of aldose reductase inhibitors (ARIs) possessing an ionizable group and/or functional group susceptible to nucleophilic attack with the aim of defining the spatial position of ARI pharmacophores. AM1 quantum chemical calculations were conducted on ARIs possessing only an ionizable group to obtain their optimized geometries. These optimized structures were then superimposed on the model compound spirofluorene-9,5'-imidazolidine-2',4'-dione (17). This superposition study suggests that a negative charge center residing in the vicinity of the 2'-oxygen of the imidazolidine-2',4'-dione ring participates in the binding interactions. In addition, the optimized geometries of ARIs possessing both an ionizable group and an electronegative functional group were superimposed on spirofluorene-9,5'-imidazolidine-2',4'-dione (17). The latter results also suggest the presence of a region where nucleophilic substitution can occur.
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Y S
authors.initials: YS
authors.lastname: Lee
authors.forename: R
authors.initials: R
authors.lastname: Pearlstein
authors.forename: P F
authors.initials: PF
authors.lastname: Kador
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D013141:Spiro Compounds; D000449:Aldehyde Reductase