Abstract
Two compounds previously isolated from traditional Chinese medicine, Menispermum dauricum (DC), 6-hydroxyl-oxoisoaporphine (H-La), and 4,6-di(2-pyridinyl)benzo[h]isoindolo[4,5,6-de]quinolin-8(5H)-one (H-Lb), were known to have in vitro antitumor activity and to selectively bind human telomeric, c-myc, and bcl-2 G-quadruplexes (G4s). In this study, the binding properties of these two compounds to telomerase were investigated through molecular docking and telomeric repeat amplication protocol and silver staining assay (TRAP-silver staining assay). The binding energies bound to human telomerase RNA were calculated by molecular docking to be −6.43 and −9.76 kcal/mol for H-La and H-Lb, respectively. Compared with H-La, the ligand H-Lb more strongly inhibited telomerase activity in the SK-OV-3 cells model.
Highlights
Previous studies found that telomerase enzyme complexes or telomerase inhibitors play a key role in tumorigenesis and telomere maintenance, and suggested that these structures may be an entry point for devising novel anticancer drugs [1,2,3]
Human telomerase is the enzyme maintains the length of telomeres, which mainly consists reverse that maintains the length of telomeres, which mainly consistsofofthree threecomponents: components: aa core core reverse transcriptase protein transcriptase protein, telomerase telomerase RNA
The human normal liver cell line HL-7702 and the human cancer cell lines HCT-8, T-24, SK-OV-3/DDP, Hep-G2, SK-OV-3, BEL-7402, and NCI-H460 were obtained from the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (Shanghai, China)
Summary
Previous studies found that telomerase enzyme complexes or telomerase inhibitors play a key role in tumorigenesis and telomere maintenance, and suggested that these structures may be an entry point for devising novel anticancer drugs [1,2,3]. A promising method among them aims to disrupt the telomere–telomerase interaction with small molecules as interfering ligands. The ligand binds the enzyme substrate to prevent telomere elongation or formation of the telomere–telomerase complex [4,5]. Small molecules that selectively bind and stabilize these structures (e.g., telomeric G4 and other G4s DNA) can influence telomere maintenance and potentially serve as therapeutic agents [1,2,3,4,5,6,7,8,9]
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