title: Structure-Based Discovery of 1H-Indazole-3-carboxamides as a Novel Structural Class of Human GSK-3 Inhibitors.
abstract: An in silico screening procedure was performed to select new inhibitors of glycogen synthase kinase 3β (GSK-3β), a serine/threonine protein kinase that in the last two decades has emerged as a key target in drug discovery, having been implicated in multiple cellular processes and linked with the pathogenesis of several diseases. GSK-3β inhibitors might prove useful as therapeutic compounds in the treatment of conditions associated with elevated levels of enzyme activity, such as type-2 diabetes and neurological disorders, for example, Alzheimer's disease, bipolar disorder, neuronal cell death, stroke, and depression. In this work, virtual screening studies were applied to proprietary compound libraries, and the functional activities of selected compounds were assayed on human GSK-3β. The in silico screening procedure enabled the identification of eight hit compounds showing pIC50 values ranging from 4.9 to 5.5. X-ray crystallographic studies resulted in a 2.50 Å three-dimensional structure of GSK-3β complexed with one of the selected compounds, confirming that the inhibitor interacts with the enzyme according to the docking hypothesis. Importantly, molecular docking was able to find a new chemical scaffold for GSK-3β inhibition, providing grounds for rational structure-based design aimed at further optimization of the initial hits.
authors.affiliation: R&D, Computational Chemistry Laboratory, ‡Chemistry Department, and §In Vitro Pharmacology Development, Angelini Research Center, ACRAF S.p.A. , Piazzale della Stazione, snc, I-00071 Santa Palomba, Pomezia (RM), Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Ombrato
authors.affiliation: R&D, Computational Chemistry Laboratory, ‡Chemistry Department, and §In Vitro Pharmacology Development, Angelini Research Center, ACRAF S.p.A. , Piazzale della Stazione, snc, I-00071 Santa Palomba, Pomezia (RM), Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cazzolla
authors.affiliation: R&D, Computational Chemistry Laboratory, ‡Chemistry Department, and §In Vitro Pharmacology Development, Angelini Research Center, ACRAF S.p.A. , Piazzale della Stazione, snc, I-00071 Santa Palomba, Pomezia (RM), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.affiliation: R&D, Computational Chemistry Laboratory, ‡Chemistry Department, and §In Vitro Pharmacology Development, Angelini Research Center, ACRAF S.p.A. , Piazzale della Stazione, snc, I-00071 Santa Palomba, Pomezia (RM), Italy.
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mangano
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003606:Dacarbazine / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D008024:Ligands; D003606:Dacarbazine; D038362:Glycogen Synthase Kinase 3