Discovery of a natural product-like c-myc G-quadruplex DNA groove-binder by molecular docking.
The natural product-like carbamide (1) has been identified as a stabilizer of the c-myc G-quadruplex through high-throughput virtual screening. NMR and molecular modeling experiments revealed a groove-binding mode for 1. The biological activity of 1 against the c-myc G-quadruplex was confirmed by its ability to inhibit Taq polymerase-mediated DNA extension and c-myc expression in vitro, demonstrating that 1 is able to control c-myc gene expression at the transcriptional level presumably through the stabilization of the c-myc promoter G-quadruplex. Furthermore, the interaction between carbamide analogues and the c-myc G-quadruplex was also investigated by in vitro experiments in order to generate a brief structure-activity relationship (SAR) for the observed potency of carbamide 1.
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Dik-Lung
DL
Ma
Daniel Shiu-Hin
DS
Chan
Wai-Chung
WC
Fu
Hong-Zhang
HZ
He
Hui
H
Yang
Siu-Cheong
SC
Yan
Chung-Hang
CH
Leung
D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D054856:G-Quadruplexes / Q000187:drug effects*; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
D001688:Biological Products; D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D014508:Urea