Structure-based virtual screening of novel natural alkaloid derivatives as potential binders of h-telo and c-myc DNA G-quadruplex conformations.
Roberta Rocca,Federica Moraca,Giosuè Costa,Stefano Alcaro,Simona Distinto,Elias Maccioni,Francesco Ortuso,Anna Artese,Lucia Parrotta +8 more
Reads0
Chats0
TLDR
In this paper, the authors performed a high throughput in silico screening of commercially available alkaloid derivative databases by means of a structure-based approach based on docking and molecular dynamics simulations against the human telomeric sequence d[AG3(T2AG3)3] and the c-myc promoter structure.Abstract:
Several ligands can bind to the non-canonical G-quadruplex DNA structures thereby stabilizing them. These molecules can act as effective anticancer agents by stabilizing the telomeric regions of DNA or by regulating oncogene expression. In order to better interact with the quartets of G-quadruplex structures, G-binders are generally characterized by a large aromatic core involved in π-π stacking. Some natural flexible cyclic molecules from Traditional Chinese Medicine have shown high binding affinity with G-quadruplex, such as berbamine and many other alkaloids. Using the structural information available on G-quadruplex structures, we performed a high throughput in silico screening of commercially available alkaloid derivative databases by means of a structure-based approach based on docking and molecular dynamics simulations against the human telomeric sequence d[AG3(T2AG3)3] and the c-myc promoter structure. We identified 69 best hits reporting an improved theoretical binding affinity with respect to the active set. Among them, a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc.read more
Citations
More filters
Journal ArticleDOI
Biological properties and clinical applications of berberine
TL;DR: Berberine shows potent neuroprotective effects, including antioxidative, antiapoptotic, and anti-ischemic, and berberine exerts protective effects against other diseases.
Journal ArticleDOI
Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations
Federica Moraca,Jussara Amato,Francesco Ortuso,Anna Artese,Bruno Pagano,Ettore Novellino,Stefano Alcaro,Michele Parrinello,Michele Parrinello,Vittorio Limongelli,Vittorio Limongelli +10 more
TL;DR: FM simulations have elucidated the binding mechanism of the anticancer alkaloid berberine to the human telomeric G4 and computed a quantitatively well-characterized free-energy landscape that allows identifying two low-energy ligand binding modes and the presence of higher energy prebinding states.
Journal ArticleDOI
New Disubstituted Quindoline Derivatives Inhibiting Burkitt's Lymphoma Cell Proliferation by Impeding c-MYC Transcription
Hui-Yun Liu,Ai-Chun Chen,Qi-Kun Yin,Zeng Li,Su-Mei Huang,Gang Du,Jin-Hui He,Li-Peng Zan,Shi-Ke Wang,Yao-Hao Xu,Jia-Heng Tan,Tian-Miao Ou,Ding Li,Lian-Quan Gu,Zhi-Shu Huang +14 more
TL;DR: Four series of disubstituted quindoline derivatives by introducing the second cationic amino side chain and 5-N-methyl group based on a previous study of SYUIQ-5 as c-MYC promoter G-quadruplex ligands exhibited higher stabilities and binding affinities and could inhibit Burkitt's lymphoma cell proliferation through cell cycle arrest and apoptosis and suppress tumor growth in a human Burkitts lymphoma xenograft.
Journal ArticleDOI
Natural Alkaloids and Heterocycles as G-Quadruplex Ligands and Potential Anticancer Agents.
TL;DR: Recent advances made by the lab in the study of G-quadruplex-targeted natural alkaloids and their derivatives toward the development of potential anticancer agents are summarized.
Journal ArticleDOI
G-quadruplex virtual drug screening: A review.
Robert C. Monsen,John O. Trent +1 more
TL;DR: A review of the past decade of G-quadruplex virtual drug discovery approaches and campaigns is provided and relevant virtual screening platforms are introduced followed by a discussion of best practices to assist future G4 VS campaigns.
References
More filters
Journal ArticleDOI
DNA and its associated processes as targets for cancer therapy
TL;DR: A new generation of agents that target DNA-associated processes are anticipated to be far more specific and effective in cancer therapeutics.
Journal ArticleDOI
G-quadruplexes in promoters throughout the human genome
TL;DR: It is shown that the promoter regions (1 kb upstream of the transcription start site TSS) of genes are significantly enriched in quadruplex motifs relative to the rest of the genome, with >40% of human gene promoters containing one or more quadruplexaterials.
Journal ArticleDOI
Inhibition of telomerase by G-quartet DNA structures.
TL;DR: Folding of telomeric DNA into G-quartet structures seems to influence the extent of telomere elongation in vitro and might therefore act as a negative regulator of lengthening in vivo.
Journal ArticleDOI
Highly prevalent putative quadruplex sequence motifs in human DNA
TL;DR: Using arithmetic ratio and probability techniques, frequent and systematic occurrence of certain sequence types are discovered, the most prominent being a potential quadruplex containing CCTGT in the first ‘loop’ position.
Journal ArticleDOI
Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops
Wesley I. Sundquist,Aaron Klug +1 more
TL;DR: This work reports that oligo-nucleotides encoding Tetrahymena telomeres dimerize to form stable complexes in solution and proposes that telomeric DNA dimerizes by hydrogen bonding between two intramolecular hairpin loops to form anti-parallel quadruplexes containing cyclic guanine base tetrads.