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-DNAShow others and affiliations
2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 11, article id 6028
Article 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)
2021-06-162021-06-162022-02-10Bibliographically approved