Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Spectroscopic and In Silico Studies on the Interaction of Substituted Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one Derivatives with c-Myc G4-DNA
Department of Chemical and Geological Sciences, University of Cagliari, Monserrato, I-09042, Italy.
Luleå University of Technology, Department of Engineering Sciences and Mathematics, Energy Science. State Key Laboratory of Materials-Oriented and Chemical Engineering, Nanjing Tech University, Nanjing, 210009, China; Division of Physical Chemistry, Department of Materials and Environmental Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, 10691, Sweden; Centre of Advanced Research in Bionanoconjugates and Biopolymers, Petru Poni Institute of Macromolecular Chemistry, Iasi, 700487, Romania.ORCID iD: 0000-0001-9783-4535
Istituto di Chimica Biomolecolare, ICB-CNR-Trav, La Crucca 3, Sassari, 07100, Italy.
Department of Chemical and Geological Sciences, University of Cagliari, Monserrato, I-09042, Italy.
Show others and affiliations
2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 11, article id 6028Article in journal (Refereed) Published
Abstract [en]

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2–4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery. 

Place, publisher, year, edition, pages
MDPI, 2021. Vol. 22, no 11, article id 6028
Keywords [en]
Anticancer drugs, C-myc, Circular dichroism, DNA quadruplexes, Docking, Molecular dynamics, Quadruplex stabilization
National Category
Biochemistry and Molecular Biology
Research subject
Energy Engineering
Identifiers
URN: urn:nbn:se:ltu:diva-85502DOI: 10.3390/ijms22116028ISI: 000660133100001PubMedID: 34199659Scopus ID: 2-s2.0-85106969708OAI: oai:DiVA.org:ltu-85502DiVA, id: diva2:1567445
Funder
Swedish Research Council, 2019-03865EU, Horizon 2020, 872331
Note

Validerad;2021;Nivå 2;2021-06-16 (beamah);

Forskningsfinansiärer: Ministry of Research and Innovation of Romania (PN-III-P4-IDPCCF-2016-0050); Regione Sardegna (RASSR 81788); Fondazione di Sardegna (F72F20000230007); Ministero dell’Istruzione, dell’Università e della Ricerca (2017W75RAE)

Available from: 2021-06-16 Created: 2021-06-16 Last updated: 2022-02-10Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMedScopus

Authority records

Laaksonen, Aatto

Search in DiVA

By author/editor
Laaksonen, Aatto
By organisation
Energy Science
In the same journal
International Journal of Molecular Sciences
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 17 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf