title: Identification of small molecular weight inhibitors of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) via in silico database screening combined with experimental assay.
abstract: Virtual screening methods combined with experimental assays were used to identify low molecular weight inhibitors for Src homology 2 domain-containing phosphatase 2 (SHP-2) that is mutated and hyperactivated in Noonan syndrome and a significant portion of childhood leukemias. Virtual screening included multiple conformations of the protein, score normalization procedures, and chemical similarity considerations. As the catalytic core of SHP-2 shares extremely high homology to those of the related SHP-1 phosphatase and other tyrosine phosphatases, in order to identify selective inhibitors, we chose to target an adjacent protein surface pocket that is predicted to be important for binding to phosphopeptides and that has structural features unique to SHP-2. From a database of 1.3 million compounds, 9 out of 165 computationally selected compounds were shown to inhibit SHP-2 activity with IC(50) values of approximately 100 microM. Two of the active compounds were further verified for their ability to inhibit SHP-2-mediated cellular functions. Fluorescence titration experiments confirmed their direct binding to SHP-2. Because of their simple chemical structures, these small organic compounds have the potential to act as lead compounds for the development of novel anti-SHP-2 drugs.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Yu
authors.forename: Olgun
authors.initials: O
authors.lastname: Guvench
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Mackerell
authors.forename: Cheng-Kui
authors.initials: CK
authors.lastname: Qu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11