title: Identification of a new STAT3 dimerization inhibitor through a pharmacophore-based virtual screening approach.
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.
authors: a Department of Pharmacy , University of Pisa , Pisa , Italy .
authors: Giulio
authors: G
authors: Poli
authors: b Department of Pharmaceutical Sciences , University of Milan , Milan , Italy , and.
authors: Arianna
authors: A
authors: Gelain
authors: b Department of Pharmaceutical Sciences , University of Milan , Milan , Italy , and.
authors: Federica
authors: F
authors: Porta
authors: c Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka , Shizuoka , Japan.
authors: Akira
authors: A
authors: Asai
authors: a Department of Pharmacy , University of Pisa , Pisa , Italy .
authors: Adriano
authors: A
authors: Martinelli
authors: a Department of Pharmacy , University of Pisa , Pisa , Italy .
authors: Tiziano
authors: T
authors: Tuccinardi
mesh_terms: D019281:Dimerization; D006801:Humans; D011487:Protein Conformation; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Docking; STAT3; pharmacophore model; virtual screening