Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ijms22116028
Keywords
circular dichroism; docking; molecular dynamics; c-myc; DNA quadruplexes; anticancer drugs; quadruplex stabilization
Funding
- European Union's Horizon 2020 research and innovation program [872331]
- Swedish Research Council [2019-03865]
- Ministry of Research and Innovation of Romania (CNCS-UEFISCDI) within PNCDI III [PN-III-P4-IDPCCF-2016-0050]
- Regione Sardegna [RASSR 81788]
- MIUR [2017W75RAE]
- Progetto Fondazione di Sardegna [CUP: F72F20000230007]
- Vinnova [2019-03865] Funding Source: Vinnova
- Swedish Research Council [2019-03865] Funding Source: Swedish Research Council
- Marie Curie Actions (MSCA) [872331] Funding Source: Marie Curie Actions (MSCA)
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This study combined experimental and in silico approaches to investigate the interaction between a series of PBTs derivatives and G-quadruplex DNA. The results showed that two out of the eight compounds induced a slight stabilizing effect on GQ, depending on the nature and position of the substituents. Additionally, Molecular Dynamics simulations at high temperatures were proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ structure.
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 degrees 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 (T(m)s). 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 T(m)s, 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.
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