title: Pharmacophore Modeling, Ensemble Docking, Virtual Screening, and Biological Evaluation on Glycogen Synthase Kinase-3β.
abstract: Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which is engaged in a variety of signaling pathways, regulating a wide range of cellular processes. GSK-3β, also known as tau protein kinase I (TPK-I), is one of the most important kinases implicated in the hyperphosphorylation of tau that leads to neurodegenerative diseases. Hence, GSK-3β has emerged as an important therapeutic target. To identify compounds that are structurally novel and diverse compared to previously reported ATP-competitive GSK-3β inhibitors, we performed virtual screening by implementing a mixed ligand/structure-based approach, which included pharmacophore modeling, diversity analysis, and ensemble docking. The sensitivities of different docking protocols to induced-fit effects were explored. An enrichment study was employed to verify the robustness of ensemble docking, using 13 X-ray structures of GSK-3β, compared to individual docking in terms of retrieving active compounds from a decoy dataset. A total of 24 structurally diverse compounds obtained from the virtual screening underwent biological validation. The bioassay results showed that 15 out of the 24 hit compounds are indeed GSK-3β inhibitors, and among them, one compound exhibiting sub-micromolar inhibitory activity is a reasonable starting point for further optimization.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS, 38677.
authors.forename: Gang
authors.initials: G
authors.lastname: Fu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS, 38677.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Sivaprakasam
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS, 38677.
authors.forename: Olivia R
authors.initials: OR
authors.lastname: Dale
authors.affiliation: National Center for Natural Products Research, University of Mississippi, University, MS, 38677. 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.|National Center for Natural Products Research, University of Mississippi, University, MS, 38677. 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. rjd@olemiss.edu.|National Center for Natural Products Research, University of Mississippi, University, MS, 38677. 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: Biological evaluation; Enrichment study; Ensemble docking; Glycogen synthase kinase-3β; Pharmacophore modeling; Virtual screening