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Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis
The interaction between the series of berberine derivatives 1–5 (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme’s activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693123/ https://www.ncbi.nlm.nih.gov/pubmed/36430540 http://dx.doi.org/10.3390/ijms232214061 |
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author | Bazzicalupi, Carla Bonardi, Alessandro Biver, Tarita Ferraroni, Marta Papi, Francesco Savastano, Matteo Lombardi, Paolo Gratteri, Paola |
author_facet | Bazzicalupi, Carla Bonardi, Alessandro Biver, Tarita Ferraroni, Marta Papi, Francesco Savastano, Matteo Lombardi, Paolo Gratteri, Paola |
author_sort | Bazzicalupi, Carla |
collection | PubMed |
description | The interaction between the series of berberine derivatives 1–5 (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme’s activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a hydrocarbon linker of varying length (n = 1–5, with n number of aliphatic carbon atoms) to the C13 position of the parent berberine. As for the G4s, both bimolecular 5′-TAGGGTTAGGGT-3′ (Tel12) and monomolecular 5′-TAGGGTTAGGGTTAGGGTTAGGG-3′ (Tel23) DNA oligonucleotides were considered. Spectrophotometric titrations, melting tests, X-ray diffraction solid state analysis and in silico molecular dynamics (MD) simulations were used to describe the different systems. The results were compared in search of structure–activity relationships. The analysis pointed out the formation of 1:1 complexes between Tel12 and all ligands, whereas both 1:1 and 2:1 ligand/G4 stoichiometries were found for the adduct formed by NAX071 (n = 1). Tel12, with tetrads free from the hindrance by the loop, showed a higher affinity. The details of the different binding geometries were discussed, highlighting the importance of H-bonds given by the berberine benzodioxole group and a correlation between the strength of binding and the hydrocarbon linker length. Theoretical (MD) and experimental (X-ray) structural studies evidence the possibility for the berberine core to interact with one or both G4 strands, depending on the constraints given by the linker length, thus affecting the G4 stabilization effect. |
format | Online Article Text |
id | pubmed-9693123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96931232022-11-26 Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis Bazzicalupi, Carla Bonardi, Alessandro Biver, Tarita Ferraroni, Marta Papi, Francesco Savastano, Matteo Lombardi, Paolo Gratteri, Paola Int J Mol Sci Article The interaction between the series of berberine derivatives 1–5 (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme’s activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a hydrocarbon linker of varying length (n = 1–5, with n number of aliphatic carbon atoms) to the C13 position of the parent berberine. As for the G4s, both bimolecular 5′-TAGGGTTAGGGT-3′ (Tel12) and monomolecular 5′-TAGGGTTAGGGTTAGGGTTAGGG-3′ (Tel23) DNA oligonucleotides were considered. Spectrophotometric titrations, melting tests, X-ray diffraction solid state analysis and in silico molecular dynamics (MD) simulations were used to describe the different systems. The results were compared in search of structure–activity relationships. The analysis pointed out the formation of 1:1 complexes between Tel12 and all ligands, whereas both 1:1 and 2:1 ligand/G4 stoichiometries were found for the adduct formed by NAX071 (n = 1). Tel12, with tetrads free from the hindrance by the loop, showed a higher affinity. The details of the different binding geometries were discussed, highlighting the importance of H-bonds given by the berberine benzodioxole group and a correlation between the strength of binding and the hydrocarbon linker length. Theoretical (MD) and experimental (X-ray) structural studies evidence the possibility for the berberine core to interact with one or both G4 strands, depending on the constraints given by the linker length, thus affecting the G4 stabilization effect. MDPI 2022-11-14 /pmc/articles/PMC9693123/ /pubmed/36430540 http://dx.doi.org/10.3390/ijms232214061 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bazzicalupi, Carla Bonardi, Alessandro Biver, Tarita Ferraroni, Marta Papi, Francesco Savastano, Matteo Lombardi, Paolo Gratteri, Paola Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis |
title | Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis |
title_full | Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis |
title_fullStr | Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis |
title_full_unstemmed | Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis |
title_short | Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis |
title_sort | probing the efficiency of 13-pyridylalkyl berberine derivatives to human telomeric g-quadruplexes binding: spectroscopic, solid state and in silico analysis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693123/ https://www.ncbi.nlm.nih.gov/pubmed/36430540 http://dx.doi.org/10.3390/ijms232214061 |
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