Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents

A molecular modeling assisted rational design and synthesis of naphthalene diimide linked bis-naphthalimides as potential DNA interactive agents is described. Chemical templates incorporating naphthalene diimide as a linker in bis-naphthalimide motif were subjected to molecular docking analysis at specific intercalation and telomeric DNA G-quadruplex sites. Excellent results were obtained, which were better than the standards. A short and convenient synthetic route was employed to access these hybrids experimentally, followed by evaluation of their ability to cause thermal denaturation of DNA and cytotoxic properties along with ADME predictions. The obtained results provided useful insights and two potential molecules were identified for further development.

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Molecular modeling and docking analysis of bis-indolymethanes derivatives as human β-glucuronidase enzyme inhibitors

Bayero Journal of Pure and Applied Sciences ◽

10.4314/bajopas.v14i1.4 ◽

2021 ◽

Vol 14 (1) ◽

pp. 21-30

Author(s):

M.T. Ibrahim ◽

U. Muhammad

Keyword(s):

Molecular Docking ◽

Physicochemical Parameters ◽

Enzyme Inhibitors ◽

Dft Method ◽

Binding Pocket ◽

Binding Mode ◽

Docking Analysis ◽

Molecular Modeling And Docking ◽

Molecular Docking Analysis ◽

Better Than

β-glucuronidase enzyme is present mostly in mammals’ tissues. β-glucuronidase is present in kidney, bile, serum, urine and spleen. In eukaryotic and prokaryotic organisms, it is important in the process of breaking down of β-glucuronide. It also helps in the neutralization of reactivity of some metabolites that are associated to many diseases. The most stable geometry of the dataset were obtained adopting DFT method at B3LYP/6-31G* level of theory. The model was developed using MLR analysis adopting GFA method. Molecular docking was also performed to portray the binding mode of these bis-indolymethanes derivatives in the binding pocket of their target receptor (human β-glucuronidase). The selected model was assessed and chosen based on its statistical fitness with R2trng=0.907233, R2adj=0.881465, Qcv2=0.833795, and R2test=0.609841. And also, the significance and impart of each physicochemical parameters to the selected model were determine by their ME values. Molecular docking analysis revealed that amino acid such as ALA49, SER52, ASP53, PHE51, VAL96, LEU92, TYR188, TYR199 and PHE200 might be responsible for the most promised binding affinity of the reported docked ligands. The molecular docking results showed that the reported compounds were better than the standard β-glucuronidase inhibitor. The results of this findings paved way for designing novel β-lucuronidase inhibitors.

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Design and synthesis of unsymmetric macrocyclic hexaoxazole compounds with an ability to induce distinct G-quadruplex topologies in telomeric DNA

Organic & Biomolecular Chemistry ◽

10.1039/c6ob00437g ◽

2016 ◽

Vol 14 (22) ◽

pp. 5109-5116 ◽

Cited By ~ 9

Author(s):

Mai Sakuma ◽

Yue Ma ◽

Yamato Tsushima ◽

Keisuke Iida ◽

Takatsugu Hirokawa ◽

...

Keyword(s):

Ring System ◽

Side Chains ◽

Telomeric Dna ◽

Macrocyclic Ring ◽

Design And Synthesis ◽

G Quadruplex

New macrocyclic hexaoxazole compounds bearing two side chains on an unsymmetrical macrocyclic ring system,i.e., 4,2-L2H2-6OTD (2) and 5,1-L2H2-6OTD (3), were designed as candidate G-quadruplex (G4) ligands and synthesized.

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Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids

Pharmaceuticals ◽

10.3390/ph15010007 ◽

2021 ◽

Vol 15 (1) ◽

pp. 7

Author(s):

Stephen Neidle

Keyword(s):

Crystal Structures ◽

Small Molecule ◽

Drug Targets ◽

Bound Water ◽

Water Molecules ◽

Telomeric Dna ◽

Naphthalene Diimide ◽

In Silico Studies ◽

G Quadruplex

The role of G-quadruplexes in human cancers is increasingly well-defined. Accordingly, G-quadruplexes can be suitable drug targets and many small molecules have been identified to date as G-quadruplex binders, some using computer-based design methods and co-crystal structures. The role of bound water molecules in the crystal structures of G-quadruplex-small molecule complexes has been analyzed in this study, focusing on the water arrangements in several G-quadruplex ligand complexes. One is the complex between the tetrasubstituted naphthalene diimide compound MM41 and a human intramolecular telomeric DNA G-quadruplex, and the others are in substituted acridine bimolecular G-quadruplex complexes. Bridging water molecules form most of the hydrogen-bond contacts between ligands and DNA in the parallel G-quadruplex structures examined here. Clusters of structured water molecules play essential roles in mediating between ligand side chain groups/chromophore core and G-quadruplex. These clusters tend to be conserved between complex and native G-quadruplex structures, suggesting that they more generally serve as platforms for ligand binding, and should be taken into account in docking and in silico studies.

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THE INFLUENCE OF UREA ON G-QUADRUPLEX AND i-MOTIF STRUCTURES IN COMPLEMENTARY DNA SEQUENCES

Proceedings of the YSU A: Physical and Mathematical Sciences ◽

10.46991/pysu:a/2020.54.2.115 ◽

2020 ◽

Vol 54 (2 (252)) ◽

pp. 115-122

Author(s):

Ye.B. Dalyan ◽

L.G. Aslanyan ◽

I.V. Vardanyan

Keyword(s):

Circular Dichroism ◽

Dna Sequences ◽

Thermal Denaturation ◽

Temperature Scale ◽

Single Strand ◽

Structural Transitions ◽

Telomeric Dna ◽

Complementary Dna ◽

G Quadruplex ◽

Circular Dichroïsm

In the present study, the methods of circular dichroism and UV/Vis spectrophotometry were used to study the influence of urea on the structural transitions i-motif $\leftrightarrows$ unfolded single strand in cytosine-rich ${\text{d[3}^{\prime}\text{-(CCCAAT)}_{3}\text{CCC-5)}^{\prime}]}$ region of telomeric DNA (Tel22C) and G-quadruplex $\leftrightarrows$ unfolded single strand in complementary guanine-rich strand ${\text{d[5}^{\prime}\text{-A(GGGTTA)}_{3}\text{GGG-3}^{\prime}]}$ (Tel22G) at pH 5.5 and 400 mM Na+. Under these conditions, Tel22C and Tel22G were found to form stable i-motif and G-quadruplex structures. It has been shown that urea (0-8 M) destabilizes the i-motif and G-quadruplex structures, but unlike thermal denaturation, it does not destroy the structures completely. The melting processes of G-quadruplex and i-motif are separated in the temperature scale (at any concentration of urea, the melting of the G-quadruplex starts at temperatures where the melting of the i-motifs has already been completed).

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Selective targeting of mutually exclusive DNA G-quadruplexes: HIV-1 LTR as paradigmatic model

Nucleic Acids Research ◽

10.1093/nar/gkaa186 ◽

2020 ◽

Vol 48 (9) ◽

pp. 4627-4642 ◽

Cited By ~ 1

Author(s):

Martina Tassinari ◽

Michela Zuffo ◽

Matteo Nadai ◽

Valentina Pirota ◽

Adriana Carolina Sevilla Montalvo ◽

...

Keyword(s):

Cellular Localization ◽

Cooperative Interaction ◽

Design And Synthesis ◽

Naphthalene Diimide ◽

Novel Approach ◽

Wide Range ◽

Selective Targeting ◽

G Quadruplex ◽

Biomolecular Assays ◽

Hiv 1

Abstract Targeting of G-quadruplexes, non-canonical conformations that form in G-rich regions of nucleic acids, has been proposed as a novel therapeutic strategy toward several diseases, including cancer and infections. The unavailability of highly selective molecules targeting a G-quadruplex of choice has hampered relevant applications. Herein, we describe a novel approach, based on naphthalene diimide (NDI)-peptide nucleic acid (PNA) conjugates, taking advantage of the cooperative interaction of the NDI with the G-quadruplex structure and hybridization of the PNA with the flanking region upstream or downstream the targeted G-quadruplex. By biophysical and biomolecular assays, we show that the NDI-PNA conjugates are able to specifically recognize the G-quadruplex of choice within the HIV-1 LTR region, consisting of overlapping and therefore mutually exclusive G-quadruplexes. Additionally, the conjugates can induce and stabilize the least populated G-quadruplex at the expenses of the more stable ones. The general and straightforward design and synthesis, which readily apply to any G4 target of choice, together with both the red-fluorescent emission and the possibility to introduce cellular localization signals, make the novel conjugates available to selectively control G-quadruplex folding over a wide range of applications.

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Design and synthesis of an antigenic mimic of the Ebola glycoprotein

Journal of Materials Research ◽

10.1557/jmr.2008.0384 ◽

2008 ◽

Vol 23 (12) ◽

pp. 3161-3168 ◽

Cited By ~ 2

Author(s):

Ryan D. Rutledge ◽

Brian J. Huffman ◽

David E. Cliffel ◽

David W. Wright

Keyword(s):

Rational Design ◽

Epitope Mapping ◽

Vaccine Development ◽

Suitable Method ◽

Design Approach ◽

Sensor Technology ◽

Native Protein ◽

Design And Synthesis ◽

Potential Applications ◽

Further Development

An antigenic mimic of the Ebola glycoprotein was synthesized and tested for its ability to be recognized by an anti-Ebola glycoprotein antibody. Epitope-mapping procedures yielded a suitable epitope that, when presented on the surface of a nanoparticle, forms a structure that is recognized by an antibody specific for the native protein. This mimic-antibody interaction has been quantitated through ELISA and QCM-based methods and yielded an affinity (Kd = 12 × 10−6 M) within two orders of magnitude of the reported affinity of the native Ebola glycoprotein for the same antibody. These results suggest that the rational design approach described herein is a suitable method for the further development of protein-based antigenic mimics with potential applications in vaccine development and sensor technology.

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