title: A combination of docking/dynamics simulations and pharmacophoric modeling to discover new dual c-Src/Abl kinase inhibitors.
abstract: A computational protocol was applied to identify molecular scaffolds untested toward the c-Src tyrosine kinase. A combination of docking and dynamics calculations allowed us to build three-dimensional models of the complexes between Src and several of its known inhibitors. Interactions most contributing to activity of the inhibitors, in terms of hydrogen bonds and hydrophobic contacts, were codified into pharmacophoric models that were in turn applied to perform a search of commercially available compounds within the Asinex database. As a result, we identified 1,3,4-thiadiazoles and pyrazolydine-3,5-diones showing inhibitory activity in the submicromolar range in a cell-free assay toward Src. Moreover, since several of the compounds used to generate pharmacophores were also known as Abl inhibitors, we tested the identified hits toward Abl tyrosine kinase, finding activity in the submicromolar range. Such biological data suggested that the computational protocol is an efficient tool for identifying new hits toward both Src and Abl.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100, Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Giada A
authors.initials: GA
authors.lastname: Locatelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Michele
authors.initials: M
authors.lastname: Modugno
authors.forename: Stefano
authors.initials: S
authors.lastname: Forli
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D006801:Humans; D008958:Models, Molecular; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry; D019061:src-Family Kinases
chemical_list: D011720:Pyrazoles; D013830:Thiadiazoles; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; C000631346:CSK protein, human