title: [Identification of low-molecular inhibitors of proteinase ASK1].
abstract: Protein kinase ASK1 (Apoptosis signal-regulating kinase 1) plays a key role in cell differentiation, aging and apoptosis. High activity of the kinase is associated with several pathologies. The ASK1 inhibitors might be therapeutic for patients with neurodegenerative, cardiovascular diseases and fibrous histiocytoma. In this work the identification of ASK1 inhibitors was performed by the methods of computer modeling and biochemical testing in vitro. The virtual screening experiments were carried out targeting the ATP binding site of ASK1 by browsing the database which contained 164 840 compounds of diverse chemical classes. The best-scored 300 ligands have been taken for the kinase assay analysis. In vitro tests revealed that derivatives of 2-thioxo-thiazolidin-4-one exhibited inhibitory activity against ASK1. The most active compound was 5-bromo-3-(4-oxo-2-thioxo-thiazolidin-5-ylidene)-1,3-dihydro-indol-2-one (IC50 = 2 microM). Binding mode for inhibitors of this class with ASK1 ATP-binding site was proposed. Our results can be used for further optimization and developing more potent and selective inhibitors of ASK1.
authors.forename: G P
authors.initials: GP
authors.lastname: Volynets
authors.forename: V G
authors.initials: VG
authors.lastname: Bdzhola
authors.forename: O P
authors.initials: OP
authors.lastname: Kukharenko
authors.forename: S M
authors.initials: SM
authors.lastname: Iarmoliuk
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D057166:High-Throughput Screening Assays; D018219:Histiocytoma, Benign Fibrous / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D010758:Phosphorus / Q000032:analysis / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D021281:Quantitative Structure-Activity Relationship; D011849:Radioactive Tracers; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D011849:Radioactive Tracers; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D045162:Thiazolidinediones; D010758:Phosphorus; D000255:Adenosine Triphosphate; D048848:MAP Kinase Kinase Kinase 5