title: Structure-based virtual screening and characterization of a novel IL-6 antagonistic compound from synthetic compound database.
abstract: According to the three-dimensional (3D) complex structure of (hIL-6⋅hIL-6R⋅gp 130)2and the binding orientation of hIL-6, three compounds with high affinity to hIL-6R and bioactivity to block hIL-6 in vitro were screened theoretically from the chemical databases, including 3D-Available Chemicals Directory (ACD) and MDL Drug Data Report (MDDR), by means of the computer-guided virtual screening method. Using distance geometry, molecular modeling and molecular dynamics trajectory analysis methods, the binding mode and binding energy of the three compounds were evaluated theoretically. Enzyme-linked immunosorbent assay analysis demonstrated that all the three compounds could block IL-6 binding to IL-6R specifically. However, only compound 1 could effectively antagonize the function of hIL-6 and inhibit the proliferation of XG-7 cells in a dose-dependent manner, whereas it showed no cytotoxicity to SP2/0 or L929 cells. These data demonstrated that the compound 1 could be a promising candidate of hIL-6 antagonist.
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Qiao
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.affiliation: First Affiliated Hospital of PLA General Hospital, Beijing, People's Republic of China.
authors.forename: Tinghuan
authors.initials: T
authors.lastname: Fu
authors.affiliation: Department of Molecular Immunology, Beijing Institute of Basic Medical Sciences.
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D062126:Databases, Chemical; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
chemical_list: D000093242:Interleukin-6 Inhibitors
keywords: XG-7 cells; apoptosis; human interlukin-6; small molecular antagonist; structural optimization; virtual screening