title: Pharmacophore-based screening and drug repurposing exemplified on glycogen synthase kinase-3 inhibitors.
abstract: The current study was conducted to elaborate a novel pharmacophore model to accurately map selective glycogen synthase kinase-3 (GSK-3) inhibitors, and perform virtual screening and drug repurposing. Pharmacophore modeling was developed using PHASE on a data set of 203 maleimides. Two benchmarking validation data sets with focus on selectivity were assembled using ChEMBL and PubChem GSK-3 confirmatory assays. A drug repurposing experiment linking pharmacophore matching with drug information originating from multiple data sources was performed. A five-point pharmacophore model was built consisting of a hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H), and two rings (RR). An atom-based 3D quantitative structure-activity relationship (QSAR) model showed good correlative and satisfactory predictive abilities (training set [Formula: see text]; test set: [Formula: see text]; whole data set: stability [Formula: see text]). Virtual screening experiments revealed that selective GSK-3 inhibitors are ranked preferentially by Hypo-1, but fail to retrieve nonselective compounds. The pharmacophore and 3D QSAR models can provide assistance to design novel, potential GSK-3 inhibitors with high potency and selectivity pattern, with potential application for the treatment of GSK-3-driven diseases. A class of purine nucleoside antileukemic drugs was identified as potential inhibitor of GSK-3, suggesting the reassessment of the target range of these drugs.
authors.affiliation: Department of Computational Chemistry, The Institute of Chemistry Timisoara of Romanian Academy, 24 Mihai Viteazul Avenue, 300223, Timisoara, Romania.
authors.forename: Luminita
authors.initials: L
authors.lastname: Crisan
authors.affiliation: Department of Computational Chemistry, The Institute of Chemistry Timisoara of Romanian Academy, 24 Mihai Viteazul Avenue, 300223, Timisoara, Romania.
authors.forename: Sorin
authors.initials: S
authors.lastname: Avram
authors.affiliation: Department of Computational Chemistry, The Institute of Chemistry Timisoara of Romanian Academy, 24 Mihai Viteazul Avenue, 300223, Timisoara, Romania. pacureanu@acad-icht.tm.edu.ro.
authors.forename: Liliana
authors.initials: L
authors.lastname: Pacureanu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007938:Leukemia / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3
keywords: Atom-based 3D QSAR; Benchmarking validation data set; GSK-3 inhibitors; Pharmacophore; Repurposing