scholarly journals New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study

2021 ◽  
Vol 14 (7) ◽  
pp. 669
Author(s):  
Enrico Cadoni ◽  
Pedro R. Magalhães ◽  
Rita M. Emídio ◽  
Eduarda Mendes ◽  
Jorge Vítor ◽  
...  
Keyword(s):  
Small Molecules ◽  
Gene Promoter ◽  
Ras Gene ◽  
Dynamic Simulations ◽  
Dna Polymerization ◽  
Structure Activity ◽  
Parallel Structures ◽  
Wide Range ◽  
G Quadruplex ◽  
Potential Applications

G-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also as sensors of quadruplex structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure–activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4, a 21-nt sequence present in human telomeres. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds’ ability to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymerization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Molecular dynamic simulations with the parallel G4 formed by a 21-nt sequence present in k-RAS gene promoter, showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.

scholarly journals New (Iso)Quinolinyl-Pyridine-2,6-dicarboxamide G-Quadruplex Ligands. A Structure-Activity Relationship Study

2021 ◽  
Author(s):  
Enrico Cadoni ◽  
Pedro R. Magalhães ◽  
Rita M. Emídio ◽  
Eduarda Mendes ◽  
Jorge B. Vítor ◽  
...  
Keyword(s):  
Small Molecules ◽  
Thermal Denaturation ◽  
Positive Charge ◽  
Quinoline Ring ◽  
Dynamic Simulations ◽  
Structure Activity ◽  
Parallel Structures ◽  
G Quadruplex ◽  
Relationship Study ◽  
Wide Potential

Quadruplex-interactive small molecules have a wide potential application, not only as drugs but also as sensors of quadruplexes structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure-activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds capacity to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymer-ization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Mo-lecular dynamic simulations with the parallel k-RAS G4 structure showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.

scholarly journals Catalytic Activities of Multimeric G-Quadruplex DNAzymes

Catalysts ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 613 ◽  
Author(s):  
Raphael I. Adeoye ◽  
Dunsin S. Osalaye ◽  
Theresia K. Ralebitso-Senior ◽  
Amanda Boddis ◽  
Amanda J. Reid ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Catalytic Efficiency ◽  
Parallel Structure ◽  
Peroxidase Mimic ◽  
Catalytic Activities ◽  
Synergistic Interactions ◽  
Parallel Structures ◽  
Wide Range ◽  
G Quadruplex ◽  
Potential Applications

G-quadruplex DNAzymes are short DNA aptamers with repeating G4 quartets bound in a non-covalent complex with hemin. These G4/Hemin structures exhibit versatile peroxidase-like catalytic activity with a wide range of potential applications in biosensing and biotechnology. Current efforts are aimed at gaining a better understanding of the molecular mechanism of DNAzyme catalysis as well as devising strategies for improving their catalytic efficiency. Multimerisation of discrete units of G-quadruplexes to form multivalent DNAzyes is an emerging design strategy aimed at enhancing the peroxidase activities of DNAzymes. While this approach holds promise of generating more active multivalent G-quadruplex DNAzymes, few examples have been studied and it is not clear what factors determine the enhancement of catalytic activities of multimeric DNAzymes. In this study, we report the design and characterisation of multimers of five G-quadruplex sequences (AS1411, Bcl-2, c-MYC, PS5.M and PS2.M). Our results show that multimerisation of G-quadruplexes that form parallel structure (AS1411, Bcl-2, c-MYC) leads to significant rate enhancements characteristic of cooperative and/or synergistic interactions between the monomeric units. In contrast, multimerisation of DNA sequences that form non-parallel structures (PS5.M and PS2.M) did not exhibit similar levels of synergistic increase in activities. These results show that design of multivalent G4/Hemin structures could lead to a new set of versatile and efficient DNAzymes with enhanced capacity to catalyse peroxidase-mimic reactions.

scholarly journals Insights into I-motif stabilization by high resolution primer extension assays: Its strengths and limitations

2022 ◽  
Author(s):  
Jan Jamroskovic ◽  
Marco Deiana ◽  
Nasim Sabouri
Keyword(s):  
High Resolution ◽  
Small Molecules ◽  
Primer Extension ◽  
Base Pairs ◽  
Promising Candidate ◽  
Experimental Conditions ◽  
Biologically Relevant ◽  
Wide Range ◽  
G Quadruplex ◽  
The Stability

Cytosine-rich DNA can fold into four-stranded intercalated structures, i-motif (iM), in acidic pH and require hemi-protonated C:C+ base pairs to form. However, its formation and stability rely on many other factors that are not yet fully understood. In here, we combined biochemical and biophysical approaches to determine the factors influencing iM stability in a wide range of experimental conditions. By using high resolution primer extension assays, circular dichroism and absorption spectroscopies, we demonstrate that the stability of three different biologically relevant iMs are not dependent on molecular crowding agents. Instead, some crowding agents affected overall DNA synthesis. We also tested a range of small molecules to determine their effect on iM stabilization at physiological temperature, and demonstrated that the G-quadruplex-specific molecule, CX-5461, is also a promising candidate for selective iM stabilization. This work provides important insights into the requirements needed for different assays to accurately study iM stabilization, which will serve as important tools for understanding biological roles of iMs and their potential as therapeutic targets.

Vitex Diterpenoids: Structural Diversity and Pharmacological Activity

2020 ◽  
Vol 26 (1) ◽  
pp. 138-159 ◽  
Author(s):  
Yanfei Ban ◽  
Tianshuang Xia ◽  
Rui Jing ◽  
Yaoli Guo ◽  
Yiya Geng ◽  
...  
Keyword(s):  
Pharmacological Activity ◽  
Hormone Level ◽  
Biological Activities ◽  
Folk Medicine ◽  
Structural Diversity ◽  
Pharmacological Activities ◽  
Structure Activity ◽  
Wide Range ◽  
Potential Applications

Plants of the genus Vitex (Verbenaceae) are mainly distributed throughout tropical and temperate regions, and many Vitex plants have been traditionally used in folk medicine. Plants of this genus are a rich source of diterpenoids, which not only displayed versatile structural diversity with potential chemotaxonomical significance but also exhibited a wide range of biological activities, mainly including in vitro cytotoxic, antiinflammatory, antimicrobial, hormone level-regulating and antiangiogenic activities. Recently, a series of bioactive diterpenoids, with interesting carbon skeletons, have been reported and gathered considerable interest. This article systematically reviewed diterpenoids isolated from the genus Vitex that appeared in the literature up to December 2018, critically highlighting their structural diversity and pharmacological activities. Up to now, a total of 154 diterpenoids with diverse structures have been isolated and identified from Vitex plants. The authors also summarized the reported structure-activity relationships of those well explored Vitex diterpenoids. Finally, the authors discussed the challenges and potential applications of these diterpenoids in the future.

Understanding Conformational Entropy in Small Molecules

2020 ◽  
Author(s):  
Lucian Chan ◽  
Garrett Morris ◽  
Geoffrey Hutchison
Keyword(s):  
Small Molecules ◽  
Degrees Of Freedom ◽  
Absolute Error ◽  
Low Energy ◽  
Standard Entropy ◽  
Free Energies ◽  
Conformational Entropy ◽  
Wide Range ◽  
High Degree ◽  
Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

Hybrid Imidazole-Pyridine Derivatives: An Approach to Novel Anticancer DNA Intercalators

2020 ◽  
Vol 27 (1) ◽  
pp. 154-169 ◽  
Author(s):  
Claudiu N. Lungu ◽  
Bogdan Ionel Bratanovici ◽  
Maria Mirabela Grigore ◽  
Vasilichia Antoci ◽  
Ionel I. Mangalagiu
Keyword(s):  
Experimental Data ◽  
Antimicrobial Properties ◽  
Qsar Model ◽  
Therapeutic Effectiveness ◽  
Computational Results ◽  
Pyridine Derivatives ◽  
Quadruplex Dna ◽  
Dna Intercalators ◽  
Structure Activity ◽  
G Quadruplex

Lack of specificity and subsequent therapeutic effectiveness of antimicrobial and antitumoral drugs is a common difficulty in therapy. The aim of this study is to investigate, both by experimental and computational methods, the antitumoral and antimicrobial properties of a series of synthesized imidazole-pyridine derivatives. Interaction with three targets was discussed: Dickerson-Drew dodecamer (PDB id 2ADU), G-quadruplex DNA string (PDB id 2F8U) and DNA strain in complex with dioxygenase (PDB id 3S5A). Docking energies were computed and represented graphically. On them, a QSAR model was developed in order to further investigate the structure-activity relationship. Results showed that synthesized compounds have antitumoral and antimicrobial properties. Computational results agreed with the experimental data.

Computational and Experimental Binding Mechanism of DNA-drug Interactions

2019 ◽  
Vol 24 (32) ◽  
pp. 3739-3757 ◽  
Author(s):  
Chandrabose Selvaraj ◽  
Sanjeev K. Singh
Keyword(s):  
Small Molecules ◽  
Self Assembly ◽  
Genetic Material ◽  
Dna Interaction ◽  
Significant Feature ◽  
Drug Molecules ◽  
Potential Applications ◽  
Novel Drug ◽  
Groove Binders ◽  
Molecular Docking And Dynamics

Nucleic acid is the key unit and a predominant genetic material for interpreting the fundamental basis of genetic information in an organism and now it is used for the evolution of a novel group of therapeutics. To identify the potential impact on the biological science, it receives high recognition in therapeutic applications. Due to its selective recognition of molecular targets and pathways, DNA significantly imparts tremendous specificity of action. Examining the properties of DNA holds numerous advantages in assembly, interconnects, computational elements, along with potential applications of DNA self-assembly and scaffolding include nanoelectronics, biosensors, and programmable/autonomous molecular machines. The interaction of low molecular weight, small molecules with DNA is a significant feature in pharmacology. Based on the mode of binding mechanisms, small molecules are categorized as intercalators and groove binders having a significant role in target-based drug development. The understanding mechanism of drug-DNA interaction plays an important role in the development of novel drug molecules with more effective and lesser side effects. This article attempts to outline those interactions of drug-DNA with both experimental and computational advances, including ultraviolet (UV) -visible spectroscopy, fluorescent spectroscopy, circular dichroism, nuclear magnetic resonance (NMR), molecular docking and dynamics, and quantum mechanical applications.

Antineoplastic Activity, Structural Modification, Synthesis and Structure-activity Relationship of Dammarane-type Ginsenosides: An Overview

2019 ◽  
Vol 23 (5) ◽  
pp. 503-516 ◽  
Author(s):  
Qiang Zhang ◽  
Xude Wang ◽  
Liyan Lv ◽  
Guangyue Su ◽  
Yuqing Zhao
Keyword(s):  
Structural Modification ◽  
Gastrointestinal Disease ◽  
Structure Activity Relationship ◽  
Cerebrovascular Diseases ◽  
Activity Relationship ◽  
Cycle Arrest ◽  
Structure Activity ◽  
Wide Range ◽  
Structural Association ◽  
Relationship Of

Dammarane-type ginsenosides are a class of tetracyclic triterpenoids with the same dammarane skeleton. These compounds have a wide range of pharmaceutical applications for neoplasms, diabetes mellitus and other metabolic syndromes, hyperlipidemia, cardiovascular and cerebrovascular diseases, aging, neurodegenerative disease, bone disease, liver disease, kidney disease, gastrointestinal disease and other conditions. In order to develop new antineoplastic drugs, it is necessary to improve the bioactivity, solubility and bioavailability, and illuminate the mechanism of action of these compounds. A large number of ginsenosides and their derivatives have been separated from certain herbs or synthesized, and tested in various experiments, such as anti-proliferation, induction of apoptosis, cell cycle arrest and cancer-involved signaling pathways. In this review, we have summarized the progress in structural modification, shed light on the structure-activity relationship (SAR), and offered insights into biosynthesis-structural association. This review is expected to provide a preliminary guide for the modification and synthesis of ginsenosides.

Studies on the EC50 of Natural Monoterpenes as Fungal Inhibitors with Quantitative Structure-Activity Relationships (QSARs)

2020 ◽  
Vol 10 (1) ◽  
pp. 44-60
Author(s):  
Mohamed E.I. Badawy ◽  
Entsar I. Rabea ◽  
Samir A.M. Abdelgaleil
Keyword(s):  
Biological Activity ◽  
Plant Pathogens ◽  
Molecular Descriptors ◽  
Microbial Pathogens ◽  
Quantitative Structure ◽  
Qsar Study ◽  
Qsar Analysis ◽  
Pharmacophore Modelling ◽  
Structure Activity ◽  
Wide Range

Background:Monoterpenes are the main constituents of the essential oils obtained from plants. These natural products offered wide spectra of biological activity and extensively tested against microbial pathogens and other agricultural pests.Methods:Antifungal activity of 10 monoterpenes, including two hydrocarbons (camphene and (S)- limonene) and eight oxygenated hydrocarbons ((R)-camphor, (R)-carvone, (S)-fenchone, geraniol, (R)-linalool, (+)-menthol, menthone, and thymol), was determined against fungi of Alternaria alternata, Botrytis cinerea, Botryodiplodia theobromae, Fusarium graminearum, Phoma exigua, Phytophthora infestans, and Sclerotinia sclerotiorum by the mycelia radial growth technique. Subsequently, Quantitative Structure-Activity Relationship (QSAR) analysis using different molecular descriptors with multiple regression analysis based on systematic search and LOOCV technique was performed. Moreover, pharmacophore modelling was carried out using LigandScout software to evaluate the common features essential for the activity and the hypothetical geometries adopted by these ligands in their most active forms.Results:The results showed that the antifungal activities were high, but depended on the chemical structure and the type of microorganism. Thymol showed the highest effect against all fungi tested with respective EC50 in the range of 10-86 mg/L. The QSAR study proved that the molecular descriptors HBA, MR, Pz, tPSA, and Vp were correlated positively with the biological activity in all of the best models with a correlation coefficient (r) ≥ 0.98 and cross-validated values (Q2) ≥ 0.77.Conclusion:The results of this work offer the opportunity to choose monoterpenes with preferential antimicrobial activity against a wide range of plant pathogens.

scholarly journals A Slot-Die Technique for the Preparation of Continuous, High-Area, Chitosan-Based Thin Films

Polymers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1566
Author(s):  
Oliver J. Pemble ◽  
Maria Bardosova ◽  
Ian M. Povey ◽  
Martyn E. Pemble
Keyword(s):  
Thin Films ◽  
Mechanical Properties ◽  
High Volume ◽  
Mechanical Anisotropy ◽  
Diverse Range ◽  
Direction Parallel ◽  
High Area ◽  
Wide Range ◽  
Slot Die ◽  
Potential Applications

Chitosan-based films have a diverse range of potential applications but are currently limited in terms of commercial use due to a lack of methods specifically designed to produce thin films in high volumes. To address this limitation directly, hydrogels prepared from chitosan, chitosan-tetraethoxy silane, also known as tetraethyl orthosilicate (TEOS) and chitosan-glutaraldehyde have been used to prepare continuous thin films using a slot-die technique which is described in detail. By way of preliminary analysis of the resulting films for comparison purposes with films made by other methods, the mechanical strength of the films produced was assessed. It was found that as expected, the hybrid films made with TEOS and glutaraldehyde both show a higher yield strength than the films made with chitosan alone. In all cases, the mechanical properties of the films were found to compare very favorably with similar measurements reported in the literature. In order to assess the possible influence of the direction in which the hydrogel passes through the slot-die on the mechanical properties of the films, testing was performed on plain chitosan samples cut in a direction parallel to the direction of travel and perpendicular to this direction. It was found that there was no evidence of any mechanical anisotropy induced by the slot die process. The examples presented here serve to illustrate how the slot-die approach may be used to create high-volume, high-area chitosan-based films cheaply and rapidly. It is suggested that an approach of the type described here may facilitate the use of chitosan-based films for a wide range of important applications.

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