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
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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
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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
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Aryl ethynyl anthraquinones: a useful platform for targeting telomeric G-quadruplex structures.
Claudia Percivalle,Claudia Sissi,Maria Laura Greco,Caterina Musetti,Angelica Mariani,Anna Artese,Giosuè Costa,Maria Lucia Perrore,Stefano Alcaro,Mauro Freccero +9 more
TL;DR: Aryl ethynyl anthraquinones have been synthesized by Sonogashira cross-coupling and evaluated as telomeric G-quadruplex ligands, by the FRET melting assay, circular dichroism, the DNA synthesis arrest assay and molecular docking.
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Toward the design of new DNA G-quadruplex ligands through rational analysis of polymorphism and binding data
Anna Artese,Giosuè Costa,Simona Distinto,Federica Moraca,Francesco Ortuso,Lucia Parrotta,Stefano Alcaro +6 more
TL;DR: Among the studied binders, a trisubstituted acridine and a dibenzophenanthroline derivative were well recognized by the parallel and the mixed G- quadruplex structures, allowing the identification of specific key contacts with DNA and the further design of more potent or target specific G-quadruplex ligands.
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Docking based virtual screening and molecular dynamics study to identify potential monoacylglycerol lipase inhibitors
TL;DR: In this article, the authors presented hybrid ligand and structure-based approaches to obtain a novel set of virtual leads as MAGL inhibitors, which showed significant binding affinity towards MAGL protein.
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Identification of New Natural DNA G-Quadruplex Binders Selected by a Structure-Based Virtual Screening Approach
TL;DR: A high throughput in silico screening of commercially natural compounds databases by means of a structure-based approach followed by docking experiments against the human telomeric sequence d[AG3(T2AG3)3] identified 12 best hits characterized by different chemical scaffolds and conformational and physicochemical properties.
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Tetraplex DNA specific ligands based on the fluorenone-carboxamide scaffold.
Stefano Alcaro,Anna Artese,Jim Iley,Rosanna Maccari,Sotiris Missailidis,Francesco Ortuso,Rosaria Ottanà,Patricia A. Ragazzon,Maria Gabriella Vigorita +8 more
TL;DR: A series of fluorenone-carboxamide compounds was analyzed with regard to DNA binding properties by UV spectroscopy and competition dialysis methods, proposing a model for the rational design of new agents with potent and selective DNA tetraplex binding properties.