scholarly journals On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5446
Author(s):  
Francesca Binacchi ◽  
Federica Guarra ◽  
Damiano Cirri ◽  
Tiziano Marzo ◽  
Alessandro Pratesi ◽  
...  
Keyword(s):  
Electrostatic Interactions ◽  
Silver Chloride ◽  
Binding Mode ◽  
Heterocyclic Carbenes ◽  
Groove Binding ◽  
Double Stranded Dna ◽  
G Quadruplex ◽  
Gold Compounds ◽  
Geometrical Constraints ◽  
Fluorescence Titrations

Gold and silver N-heterocyclic carbenes (NHCs) are emerging for therapeutic applications. Multiple techniques are here used to unveil the mechanistic details of the binding to different biosubstrates of bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride [Ag(EIA)2]Cl and bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) gold chloride [Au(EIA)2]Cl. As the biosubstrates, we tested natural double-stranded DNA, synthetic RNA polynucleotides (single-poly(A), double-poly(A)poly(U) and triple-stranded poly(A)2poly(U)), DNA G-quadruplex structures (G4s), and bovine serum albumin (BSA) protein. Absorbance and fluorescence titrations, mass spectrometry together with melting and viscometry tests show significant differences in the binding features between silver and gold compounds. [Au(EIA)2]Cl covalently binds BSA. It is here evidenced that the selectivity is high: low affinity and external binding for all polynucleotides and G4s are found. Conversely, in the case of [Ag(EIA)2]Cl, the binding to BSA is weak and relies on electrostatic interactions. [Ag(EIA)2]Cl strongly/selectively interacts only with double strands by a mechanism where intercalation plays the major role, but groove binding is also operative. The absence of an interaction with triplexes indicates the major role played by the geometrical constraints to drive the binding mode.

scholarly journals Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex

2015 ◽  
Vol 112 (31) ◽  
pp. 9608-9613 ◽  
Author(s):  
Brahim Heddi ◽  
Vee Vee Cheong ◽  
Herry Martadinata ◽  
Anh Tuân Phan
Keyword(s):  
Electrostatic Interactions ◽  
Solution Structure ◽  
Binding Mode ◽  
Structural Basis ◽  
Cellular Processes ◽  
Charged Amino Acids ◽  
G Quadruplex ◽  
Guanine Base ◽  
Nucleic Acid Structures ◽  
Phosphate Groups

Four-stranded nucleic acid structures called G-quadruplexes have been associated with important cellular processes, which should require G-quadruplex–protein interaction. However, the structural basis for specific G-quadruplex recognition by proteins has not been understood. The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also named DHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identified an 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptide bound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallel G-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps the G-quadruplex using three-anchor-point electrostatic interactions between three positively charged amino acids and negatively charged phosphate groups. This binding mode is strikingly similar to that of most ligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simple and efficient way to specifically target G-quadruplex structures.

scholarly journals 9,10-Bis[(4-(2-hydroxyethyl)piperazine-1-yl)prop-2-yne-1-yl]anthracene: Synthesis and G-quadruplex Selectivity

Molbank ◽  
10.3390/m1138 ◽  
2020 ◽  
Vol 2020 (2) ◽  
pp. M1138
Author(s):  
Giovanni Ribaudo ◽  
Alberto Ongaro ◽  
Erika Oselladore ◽  
Giuseppe Zagotto ◽  
Maurizio Memo ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Binding Mode ◽  
Sonogashira Reaction ◽  
Ionization Mass ◽  
Quadruplex Dna ◽  
Anthracene Derivative ◽  
Double Stranded Dna ◽  
G Quadruplex ◽  
A3 Coupling ◽  
Hydroxyethyl Piperazine

G-quadruplex DNA is the target of several natural and synthetic small molecules with antiproliferative and antiviral activity. We here report the synthesis through Sonogashira reaction and A3 coupling of a disubstituted anthracene derivative, 9,10-bis[(4-(2-hydroxyethyl)piperazine-1-yl)prop-2-yne-1-yl]anthracene. The binding of this compound to G-quadruplex and double stranded DNA sequences was evaluated using electrospray ionization mass spectrometry (ESI-MS), demonstrating selectivity for the first structure. The interaction pattern of the ligand with G-quadruplex was investigated by molecular docking and stacking was found to be the preferred binding mode.

scholarly journals Binding of BRACO19 to a Telomeric G-Quadruplex DNA Probed by All-Atom Molecular Dynamics Simulations with Explicit Solvent

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1010 ◽  
Author(s):  
Babitha Machireddy ◽  
Holli-Joi Sullivan ◽  
Chun Wu
Keyword(s):  
Molecular Dynamics ◽  
Binding Energy ◽  
Free Ligand ◽  
Binding Mode ◽  
Dna Duplex ◽  
Telomeric Dna ◽  
Groove Binding ◽  
Relative Population ◽  
G Quadruplex ◽  
Groove Binding Mode

Although BRACO19 is a potent G-quadruplex binder, its potential for clinical usage is hindered by its low selectivity towards DNA G-quadruplex over duplex. High-resolution structures of BRACO19 in complex with neither single-stranded telomeric DNA G-quadruplexes nor B-DNA duplex are available. In this study, the binding pathway of BRACO19 was probed by 27.5 µs molecular dynamics binding simulations with a free ligand (BRACO19) to a DNA duplex and three different topological folds of the human telomeric DNA G-quadruplex (parallel, anti-parallel and hybrid). The most stable binding modes were identified as end stacking and groove binding for the DNA G-quadruplexes and duplex, respectively. Among the three G-quadruplex topologies, the MM-GBSA binding energy analysis suggested that BRACO19′s binding to the parallel scaffold was most energetically favorable. The two lines of conflicting evidence plus our binding energy data suggest conformation-selection mechanism: the relative population shift of three scaffolds upon BRACO19 binding (i.e., an increase of population of parallel scaffold, a decrease of populations of antiparallel and/or hybrid scaffold). This hypothesis appears to be consistent with the fact that BRACO19 was specifically designed based on the structural requirements of the parallel scaffold and has since proven effective against a variety of cancer cell lines as well as toward a number of scaffolds. In addition, this binding mode is only slightly more favorable than BRACO19s binding to the duplex, explaining the low binding selectivity of BRACO19 to G-quadruplexes over duplex DNA. Our detailed analysis suggests that BRACO19′s groove binding mode may not be stable enough to maintain a prolonged binding event and that the groove binding mode may function as an intermediate state preceding a more energetically favorable end stacking pose; base flipping played an important role in enhancing binding interactions, an integral feature of an induced fit binding mechanism.

DNA Photocleavage and Binding Modes of Methylene Violet 3RAX and its Derivatives: Effect of Functional Groups

2017 ◽  
Vol 70 (7) ◽  
pp. 830 ◽  
Author(s):  
Ke Yang ◽  
Xiong Zhang ◽  
Fang Yang ◽  
Fengshou Wu ◽  
Xiulan Zhang ◽  
...  
Keyword(s):  
Singlet Oxygen ◽  
Electrostatic Interactions ◽  
1H Nmr Spectroscopy ◽  
Binding Mode ◽  
Binding Modes ◽  
Oxygen Production ◽  
Groove Binding ◽  
Dna Photocleavage ◽  
Intercalative Mode ◽  
Methylene Violet

With 4′-amino-N,N-diethylaniline and aniline as starting materials, methylene violet 3RAX 1 and its derivatives 2–5 were synthesised. The five compounds were characterised by IR, UV-vis, and 1H NMR spectroscopy and mass spectrometry. The binding mode between the synthesised compounds and DNA were investigated. The results show that both compounds 1 and 5 bind to DNA by an intercalative mode, while compounds 2–4 interact with DNA through a mixed binding mode involving groove binding and electrostatic interactions. The photocleavage ability of the five compounds to DNA were calculated to be 38, 40, 30, 20, and 13 %, respectively, when their concentration was adjusted to 400 μM. The singlet oxygen production of compounds measured by the 1,3-diphenylisobenzofuran method was consistent with the trend of DNA photocleavage ability. The DNA studies suggest that the binding mode between methylene violet 3RAX and DNA, the ability of methylene violet 3RAX to generate singlet oxygen, and the DNA photocleavage activity could be adjusted through modification of the amino group on methylene violet 3RAX.

scholarly journals G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions

2021 ◽  
Vol 14 (8) ◽  
pp. 769
Author(s):  
Tiago Santos ◽  
Gilmar F. Salgado ◽  
Eurico J. Cabrita ◽  
Carla Cruz
Keyword(s):  
High Throughput ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Binding Mode ◽  
Titration Calorimetry ◽  
Apparent Affinity ◽  
G Quadruplex ◽  
Ligand Interactions ◽  
Types Of Information ◽  
Fluorescent Intercalator Displacement

Progress in the design of G-quadruplex (G4) binding ligands relies on the availability of approaches that assess the binding mode and nature of the interactions between G4 forming sequences and their putative ligands. The experimental approaches used to characterize G4/ligand interactions can be categorized into structure-based methods (circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography), affinity and apparent affinity-based methods (surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and mass spectrometry (MS)), and high-throughput methods (fluorescence resonance energy transfer (FRET)-melting, G4-fluorescent intercalator displacement assay (G4-FID), affinity chromatography and microarrays. Each method has unique advantages and drawbacks, which makes it essential to select the ideal strategies for the biological question being addressed. The structural- and affinity and apparent affinity-based methods are in several cases complex and/or time-consuming and can be combined with fast and cheap high-throughput approaches to improve the design and development of new potential G4 ligands. In recent years, the joint use of these techniques permitted the discovery of a huge number of G4 ligands investigated for diagnostic and therapeutic purposes. Overall, this review article highlights in detail the most commonly used approaches to characterize the G4/ligand interactions, as well as the applications and types of information that can be obtained from the use of each technique.

scholarly journals Novel Trimethine Cyanine Dye as Potential Amyloid Marker

2018 ◽  
Keyword(s):  
Absorption Spectra ◽  
Electrostatic Interactions ◽  
Amyloid Fibrils ◽  
Binding Mode ◽  
Docking Studies ◽  
Cyanine Dye ◽  
Dye Absorption ◽  
Self Association ◽  
A Chain ◽  
Log Normal

The applicability of the novel cyanine dye AK 3-1 to the detection and characterization of pathogenic protein aggregates, amyloid fibrils, was tested using the absorption spectroscopy technique. In an organic solvent dimethyl sulfoxide (DMSO), absorption spectra of AK3-1 exhibits vibrational structure with the relative intensity of 0-0 sub-band being higher than that for the 0-1 sub-band. In an aqueous phase the dye absorption band undergoes hypsochromic shift relative to DMSO due to H-aggregation of the dye. The interaction of AK3-1 with the native and fibrillar insulin was followed by the decrease of monomer band and the enhancement of H-dimer band. To evaluate the relative contributions of the monomeric and aggregated forms, the absorption spectra of the protein-bound dye were deconvoluted using the asymmetric log-normal (LN) function. The analysis of the set of fitting parameters provides evidence for the protein-induced AK3-1 self-association into the head-to-head dimers, with the magnitude of this effect being much more pronounced for fibrillar protein form. The molecular docking studies showed that the AK3-1 monomer tends to associate with the specific arrangement of side chains in the β-sheet formed by L17 leucine residues (of the insulin B-chain), located on the dry steric zipper interface of the fibril, while the dye dimers form stable complexes with the amyloid groove formed by the residues Q15 and E17 of the A-chain, and located on the wet interface of the fibril. The latter binding site is more easily accessible and is additionally stabilized by the electrostatic interactions between the positively charged dye and the E17 residue. This binding mode seems to be prevailing over that for the AK3-1 monomers. Based on the results obtained, AK3-1 may be recommended as a prospective amyloid marker complementary to the classical amyloid reporters Thioflavin T and Congo Red.

scholarly journals Visible-Light Photoswitching of G-Quadruplex Ligand Binding Mode Allows Reversible Control of G-Tetrad Structure

2020 ◽  
Author(s):  
Michael O'Hagan ◽  
Javier Ramos Soriano ◽  
Susanta Haldar ◽  
Juan Carlos Morales ◽  
Adrian Mulholland ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Visible Light ◽  
Uv Light ◽  
Binding Mode ◽  
High Energy ◽  
Light Sources ◽  
Biologically Relevant ◽  
G Quadruplex ◽  
Potential Applications ◽  
Robust Regulation

<div><p>Photoresponsive ligands for G-quadruplex oligonucleotides (G4) offer exciting opportunities for the reversible regulation of these assemblies with potential applications in biological chemistry and responsive nanotechnology. However, achieving the robust regulation of G4 ligand activity with low-energy visible light sources that are easily accessible and compatible with biological systems remains a significant challenge to realizing these applications. Herein, we report the G4-binding properties of a photoresponsive dithienylethene (DTE). We demonstrate the first example of G4-specific acceleration of the photoswitching kinetics of a small molecule and the visible-light mediated switching of the G4 ligand binding mode in physiologically-relevant conditions, which in turn allows control over the G4 tetrad structure of telomeric G4 in potassium buffer. The process is fully reversible and avoids the need for high-energy UV light. This affords an efficient, practical and biologically-relevant means of control that may be applied in the generation of new responsive G4/ligand supramolecular systems.</p></div><br>

scholarly journals A Complete Assessment of Dopamine Receptor-Ligand Interactions through Computational Methods

2019 ◽  
Author(s):  
Beatriz Bueschbell ◽  
Carlos A.V. Barreto ◽  
Antonio J. Preto ◽  
Anke C. Schiedel ◽  
Irina S. Moreira
Keyword(s):  
Dopamine Receptor ◽  
Electrostatic Interactions ◽  
Specific Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Receptor Subtypes ◽  
Receptor Ligand ◽  
Pi Stacking ◽  
Ligand Interactions ◽  
New Treatments

Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions &gt; 2.5 &Aring; and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions. Known residues such as 3.32Asp, the serine microdomain and the aromatic microdomain were found interacting in a variety of modes (HB, SB, &pi;-stacking). Purposed TM2-TM3-TM7 microdomain was found to form a hydrophobic network involving Orthosteric Binding Pocket (OBP) and Secondary Binding Pocket (SBP). T-stacking interactions revealed as especially relevant for some large ligands such as apomorphine, risperidone or aripiprazole. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, key for the design of more specific ligands.

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