title: Rational design of an indolebutanoic acid derivative as a novel aldose reductase inhibitor based on docking and 3D QSAR studies of phenethylamine derivatives.
abstract: A series of 45 phenethylamine derivatives were synthesized and evaluated for their inhibitory activity against pig kidney aldose reductase (ALR2, EC 1.1.1.21). Their IC(50) values ranged from 400 microM to 24 microM. The binding modes of compounds at the active site of ALR2 were examined using flexible docking. The results indicated that phenethylamine derivatives nicely fit into the active pocket of ALR2 by forming various hydrogen bonding and hydrophobic interactions. 3D-QSAR analysis was also conducted using FlexX-docked alignment of the compounds. The best prediction was obtained by CoMSIA combined with hydrophobic and hydrogen bond donor/acceptor field (q(2) = 0.557, r(2) = 0.934). A new derivative, 4-oxo-4-(4-hydroxyindole)butanoic acid, was designed, taking into account the CoMSIA field and the binding mode derived by FlexX docking. This rationally designed compound exhibits an ALR2 inhibition with an IC(50) value of 7.4 microM, which compares favorably to that of a well-known ALR2 inhibitor, tolrestat (IC(50) = 16 microM) and represents a potency approximately 240-fold higher than that of an original phenethylamine lead compound, YUA001.
authors.affiliation: Department of Biotechnology, College of Engineering and Bioproducts Research Center, Yonsei University, Seoul 120-749, Korea.
authors.forename: Won Suck
authors.initials: WS
authors.lastname: Sun
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Park
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Sung Han
authors.initials: SH
authors.lastname: Kim
authors.forename: Jung-Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007668:Kidney / Q000737:chemistry; D008958:Models, Molecular; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013552:Swine
chemical_list: C480608:4-oxo-4-(4-hydroxyindole)butanoic acid; D002087:Butyrates; D004791:Enzyme Inhibitors; D007211:Indoles; D010627:Phenethylamines; D000449:Aldehyde Reductase