Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach. (1st November 2016)

• Record Type: Journal Article
• Authors: Poli, Giulio; Gelain, Arianna; Porta, Federica; Asai, Akira; Martinelli, Adriano; Tuccinardi, Tiziano
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 31:Number 6(2016:Dec.)
• Page Start: 1011
• Page End: 1017
• Publication Date: 2016-11-01
• Subjects: Docking -- pharmacophore model -- STAT3 -- virtual screening; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2015.1079184
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Signal transducer and activator of transcription 3 (STAT3) plays an essential role in cell growth regulation and survival. An aberrant STAT3 activation and/or expression is implied in various solid and blood tumors as well as in other pathologies like rheumatoid arthritis and pulmonary fibrosis, thus making the search for STAT3 inhibitors a growing field of study. With the aim of identifying new inhibitors of STAT3 dimerization, we screened a database including more than 1 320 000 commercially available compounds using a receptor-based pharmacophore model comprising the key protein–protein interactions identified in the STAT3 dimer and refining the search through docking and molecular dynamic simulations studies. STAT3 binding assays revealed a significant STAT3 inhibitory activity and selectivity versus Grb2 for one of the four top-scored compounds, thus verifying the reliability of the virtual screening workflow. Moreover, such compound could already be considered as a lead for the development of new and more potent STAT3 dimerization inhibitors.