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

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 observe...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 22; no. 11; p. 6028
Main Authors:	Mulliri, Simone, Laaksonen, Aatto, Spanu, Pietro, Farris, Riccardo, Farci, Matteo, Mingoia, Francesco, Roviello, Giovanni N, Mocci, Francesca
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI 02-06-2021 MDPI AG
Subjects:	Anticancer drugs Binding Sites - drug effects C-myc Circular Dichroism Computer Simulation DNA - chemistry DNA - drug effects DNA - ultrastructure DNA quadruplexes Docking Energiteknik Energy Engineering G-Quadruplexes - drug effects Humans Ligands Molecular dynamics Molecular Dynamics Simulation Promoter Regions, Genetic - genetics Proto-Oncogene Proteins c-myc - chemistry Proto-Oncogene Proteins c-myc - ultrastructure Quadruplex stabilization Telomere - chemistry Telomere - drug effects Telomere - genetics docking c-myc quadruplex stabilization DNA quadruplexes circular dichroism molecular dynamics anticancer drugs
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Summary:	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 (T 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 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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ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms22116028