title: Construction and validation of a RET TK catalytic domain by homology modeling.
abstract: RET tyrosine kinase (TK) oncoproteins are potential targets for anticancer therapy. However, the search for novel RET inhibitors has been hampered by the lack of a 3D structure of the receptor. In this study, the "open" and the "closed" structure of the RET TK catalytic domain have been built by homology modeling techniques. The structures were validated by extensive docking studies with practically all the inhibitors reported in the literature and through molecular dynamics simulations of the resulting complexes. All the expected major interactions between the active domain amino acids and the inhibitors have been reproduced in their details. Furthermore, the proposed 3D models are in agreement with the results of available mutation studies. Therefore, these models could be profitably used to filter off from large libraries new potential hit compounds able to target this enzyme.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, I-56126 Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D019295:Computational Biology; D003198:Computer Simulation; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D008024:Ligands; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases