title: 3D-pharmacophore analyses of aldose reductase inhibitory spiroquinazolinones.
abstract: In order to get an insight for designing novel inhibitors of aldose reductase, we analyzed relationships between structures of spiroquinazolinones and their inhibitory activities against rabbit aldose reductase by comparative molecular field analysis and molecular modeling of the enzyme-inhibitor complex. It was revealed that the following interactions were operative for the enhancement of inhibitory activity; 1) the hydrophobic interaction between substituents at the 6'- and 7'-position of quinazolinone and the hydrophobic residues such as Trp20, Val47, Tyr48, Tyr121 and Phe122; 2) the electrostatic interaction formed between electronegative substituents at the 6'-position and the side chain of Gln49; 3) the complementary fit of sterically small 6'-substituents to the active site.
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Yodogawa, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakao
authors.forename: M
authors.initials: M
authors.lastname: Asao
authors.forename: H
authors.initials: H
authors.lastname: Shirai
authors.forename: R
authors.initials: R
authors.lastname: Shimizu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D003461:Crystallography; D066298:In Vitro Techniques; D008958:Models, Molecular; D011799:Quinazolines / Q000494:pharmacology*; D011817:Rabbits; D012995:Solubility; D055672:Static Electricity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011799:Quinazolines; D000449:Aldehyde Reductase