[Identification of low-molecular inhibitors of proteinase ASK1].

TLDR: In vitro tests revealed that derivatives of 2-thioxo-thiazolidin-4-one exhibited inhibitory activity against ASK1, and binding mode for inhibitors of this class with ASK 1 ATP-binding site was proposed, which can be used for further optimization and developing more potent and selective inhibitors of ASK2.

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.