title: Probing the physicochemical and structural requirements for glycogen synthase kinase-3alpha inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides.
abstract: Glycogen synthase kinase-3alpha (GSK-3alpha) was recently found to be an attractive target for the treatment of Alzheimer's disease due to its dual action in the formation of both amyloid plaques and neurofibrillary tangles. It is also a viable target for many other diseases, such as type 2 diabetes. Reported herein is a 2D-QSAR exploration of the physicochemical (hydrophobic, electronic, and steric) and structural requirements among 3-anilino-4-phenylmaleimides toward GSK-3alpha binding. Using Fujita-Ban and Hansch QSAR analysis, electronic and steric interactions at the 4-phenyl ring and hydrophobic interactions at the 3-anilino ring are shown to be crucial. Analysis of the 4-phenyl ring of these compounds using common aromatic substituent constants showed electron-withdrawing and bulky ortho substituents as imperative for GSK-3alpha inhibition.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677-1848, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Sivaprakasam
authors.forename: Aihua
authors.initials: A
authors.lastname: Xie
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
mesh_terms: D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008301:Maleimides / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D008301:Maleimides; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha