title: Quantitative Structure-Activity Relationship Analysis and a Combined Ligand-Based/Structure-Based Virtual Screening Study for Glycogen Synthase Kinase-3.
abstract: Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which regulates a wide range of cellular processes, involving various signalling pathways. GSK-3β has emerged as an important therapeutic target for diabetes and Alzheimer's disease. To identify structurally novel GSK-3β inhibitors, we performed virtual screening by implementing a combined ligand-based/structure-based approach, which included quantitative structure-activity relationship (QSAR) analysis and docking prediction. To integrate and analyze complex data sets from multiple experimental sources, we drafted and validated a hierarchical QSAR method, which adopts a two-level structure to take data heterogeneity into account. A collection of 728 GSK-3 inhibitors with diverse structural scaffolds was obtained from published papers that used different experimental assay protocols. Support vector machines and random forests were implemented with wrapper-based feature selection algorithms to construct predictive learning models. The best models for each single group of compounds were then used to build the final hierarchical QSAR model, with an overall R(2) of 0.752 for the 141 compounds in the test set. The compounds obtained from the virtual screening experiment were tested for GSK-3β inhibition. The bioassay results confirmed that 2 hit compounds are indeed GSK-3β inhibitors exhibiting sub-micromolar inhibitory activity, and therefore validated our combined ligand-based/structure-based approach as effective for virtual screening experiments.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA.|Department of Computer and Information Science, School of Engineering, University of Mississippi, University, MS 38677, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Fu
authors.affiliation: Department of Computer and Information Science, School of Engineering, University of Mississippi, University, MS 38677, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Computer and Information Science, School of Engineering, University of Mississippi, University, MS 38677, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Nan
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
authors.forename: Olivia R
authors.initials: OR
authors.lastname: Dale
authors.affiliation: Department of Computer and Information Science, School of Engineering, University of Mississippi, University, MS 38677, USA.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Computer and Information Science, School of Engineering, University of Mississippi, University, MS 38677, USA.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Computer and Information Science, School of Engineering, University of Mississippi, University, MS 38677, USA.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Wilkins
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Faser Hall 419, University, MS 38677, USA phone: (662)-915-5880.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Manly
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA.|National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Faser Hall 419, University, MS 38677, USA phone: (662)-915-5880.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Cutler
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677, USA. rjd@olemiss.edu.|National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Faser Hall 419, University, MS 38677, USA phone: (662)-915-5880. rjd@olemiss.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
keywords: Glycogen synthase kinase-3 inhibitors; High-throughput screening; Random forests; Structure-activity relationships; Support vector machines