title: In silico identification of novel ligands for G-quadruplex in the c-MYC promoter.
abstract: G-quadruplex DNA formed in NHEIII1 region of oncogene promoter inhibits transcription of the genes. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c-MYC. Several hit ligands showed the selective PCR-arresting effects for oligonucleotide containing c-MYC G-quadruplex forming sequence. Among them, three hits selectively inhibited cell proliferation and decreased c-MYC mRNA level in Ramos cells, where NHEIII1 is included in translocated c-MYC gene for overexpression. Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene. In conclusion, combined virtual screening methods were successfully used for discovery of selective c-MYC promoter G-quadruplex binders with anticancer activity.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, South Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D016271:Proto-Oncogene Proteins c-myc