Unravelling the binding affinity and selectivity of molybdenum(<scp>ii</scp>) phenanthroline complexes with DNA G-quadruplexes by using linear-scaling DFT studies. The important role of ancillary ligands

Luzuriaga, Iker Ortiz de; Sánchez-González, Ángel; Synoradzki, Wojciech; López, Xabier; Gil, Adrià

doi:10.1039/d2cp02241a

Cited by 5 publications

(2 citation statements)

References 82 publications

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“…Moreover, the module of the calculated binding energy of Fangchinoline with the C9-HRE P-GQ unit (−6.67 kcal/mol on average for Site 1 and Site 2) was lower than that with the dimeric P-GQs (−6.96 kcal/mol on average for Site 1 to Site 4), which is consistent with the previous binding constant result calculated by Hill fitting using the CD method, and may be caused by extra non-electrostatic interactions of Fangchinoline with the interface groove regions in the dimeric P-GQs ( Figure 6 b, Site 1 and Site 2). However, it should be noticed that the conformational flexibility is not modeled in the in silico docking process, and thus the precise interaction and the complex conformation still need further exploration using either molecular dynamics (MD) simulations, as described by Gil’s and Bhowmik’s groups [ 51 , 52 , 53 , 54 ], or NMR and crystallography studies.…”

Section: Resultsmentioning

confidence: 99%

“…binding constant result calculated by Hill fitting using the CD method, and may be caused by extra non-electrostatic interactions of Fangchinoline with the interface groove regions in the dimeric P-GQs (Figure 6b, Site 1 and Site 2). However, it should be noticed that the conformational flexibility is not modeled in the in silico docking process, and thus the precise interaction and the complex conformation still need further exploration using either molecular dynamics (MD) simulations, as described by Gil's and Bhowmik's groups [51][52][53][54], or NMR and crystallography studies.…”

Section: Fangchinoline Is a Groove-binder To The Parallel C9-hre Gqmentioning

confidence: 99%

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G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline

Zhang

Huang

et al. 2023

Molecules

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The G-quadruplex (GQ)-forming hexanucleotide repeat expansion (HRE) in the C9orf72 (C9) gene has been found to be the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (collectively, C9ALS/FTD), implying the great significance of modulating C9-HRE GQ structures in C9ALS/FTD therapeutic treatment strategies. In this study, we investigated the GQ structures formed by varied lengths of C9-HRE DNA sequences d(GGGGCC)4 (C9-24mer) and d(GGGGCC)8 (C9-48mer), and found that the C9-24mer forms anti-parallel GQ (AP-GQ) in the presence of potassium ions, while the long C9-48mer bearing eight guanine tracts forms unstacked tandem GQ consisting of two C9-24mer unimolecular AP-GQs. Moreover, the natural small molecule Fangchinoline was screened out in order to be able to stabilize and alter the C9-HRE DNA to parallel GQ topology. Further study of the interaction of Fangchinoline with the C9-HRE RNA GQ unit r(GGGGCC)4 (C9-RNA) revealed that it can also recognize and improve the thermal stability of C9-HRE RNA GQ. Finally, use of AutoDock simulation results indicated that Fangchinoline binds to the groove regions of the parallel C9-HRE GQs. These findings pave the way for further studies of GQ structures formed by pathologically related long C9-HRE sequences, and also provide a natural small-molecule ligand that modulates the structure and stability of C9-HRE GQ, both in DNA and RNA levels. Altogether, this work may contribute to therapeutic approaches of C9ALS/FTD which take the upstream C9-HRE DNA region, as well as the toxic C9-HRE RNA, as targets.

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Section: Resultsmentioning

confidence: 99%

Section: Fangchinoline Is a Groove-binder To The Parallel C9-hre Gqmentioning

confidence: 99%

G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline

Zhang

Huang

et al. 2023

Molecules

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Non‐Innocent π Linkers Affect Cooperativity in Hydrogen‐Bonded Macrocycles

Almacellas,

van der Lubbe,

Grosch

et al. 2023

ChemistryEurope

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Rigid, linear π‐conjugated acetylene linkers connecting a hydrogen‐bond acceptor to a hydrogen‐bond donor are established building blocks for self‐assembled hydrogen‐bonded macrocycles. Kohn‐Sham molecular orbital and Voronoi deformation density analyses reveal that the acetylene linker plays an unprecedented, non‐innocent role in the cooperativity of these hydrogen‐bonded macrocycles. The acetylene linker can abstract electron density from the hydrogen‐bond acceptor and donor, due to the linkers’ low‐lying π‐LUMO. As a result, the hydrogen‐bond acceptor becomes less negatively charged, which both hampers the cooperativity, as well as the hydrogen bond strength, in the hydrogen‐bonded macrocycles. This effect becomes more pronounced when the size of the acetylene linker increases. The findings presented in this work can act as design principles for the development of novel supramolecular macrocycles based on hydrogen bonds.

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Cooperativity in Hydrogen‐Bonded Macrocycles Derived from Nucleobases

Almacellas,

van der Lubbe,

Grosch

et al. 2024

Eur J Org Chem

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Introducing a rigid linear π‐conjugated acetylene linker into a supramolecular building block consisting of a hydrogen‐bond donor side and a hydrogen‐bond acceptor side yields a decrease of cooperativity in the resulting formed quartet. This follows from our Kohn‐Sham molecular orbital and Voronoi deformation density analyses of hydrogen‐bonded macrocycles based on guanine and cytosine nucleobases. The acetylene linker abstracts electron density from the hydrogen‐bond acceptor and donor, making the hydrogen‐bond acceptor become more negatively charged whereas the hydrogen‐bond donor becomes more positively charged and hence suppressing the donor–acceptor charge transfer interaction between the interacting fragments. This, ultimately, hampers the cooperativity in the hydrogen‐bonded macrocycle. We envision that these findings could open the door to new design principles for the development of novel hydrogen‐bond supramolecular macrocycles.

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Unravelling the binding affinity and selectivity of molybdenum(ii) phenanthroline complexes with DNA G-quadruplexes by using linear-scaling DFT studies. The important role of ancillary ligands

Abstract: We have used near linear-scaling density functional theory (LS-DFT) methods including dispersion, for the first time, to study the interaction of two isomers, equatorial (Eq) and axial (Ax), of the...

Cited by 5 publications

References 82 publications

G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline

G-Quadruplexes Formation by the C9orf72 Nucleotide Repeat Expansion d(GGGGCC)n and Conformation Regulation by Fangchinoline

Non‐Innocent π Linkers Affect Cooperativity in Hydrogen‐Bonded Macrocycles

Cooperativity in Hydrogen‐Bonded Macrocycles Derived from Nucleobases

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