scholarly journals Identification of Effective Anticancer G-Quadruplex-Targeting Chemotypes through the Exploration of a High Diversity Library of Natural Compounds

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1611
Author(s):  
Chiara Platella ◽  
Francesca Ghirga ◽  
Pasquale Zizza ◽  
Luca Pompili ◽  
Simona Marzano ◽  
...  
Keyword(s):  
Structural Diversity ◽  
Natural Compounds ◽  
Interaction Patterns ◽  
Screening Assay ◽  
Biological Assays ◽  
G Quadruplex ◽  
Biophysical Studies ◽  
Selective Interaction ◽  
Dynamics Simulations ◽  
High Diversity

In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural compounds have been thus far poorly explored, though representing appealing candidates due to the high structural diversity of their scaffolds. In this regard, a unique high diversity in-house library composed of ca. one thousand individual natural products was investigated. The combination of molecular docking-based virtual screening and the G4-CPG experimental screening assay proved to be useful to quickly and effectively identify—out of many natural compounds—five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously demonstrated the selective interaction of these compounds with G4s compared to duplex DNA. The rationale behind the G4 selective recognition was suggested by molecular dynamics simulations. Indeed, the selected ligands proved to specifically interact with G4 structures due to peculiar interaction patterns, while they were unable to firmly bind to a DNA duplex. From biological assays, Chelidonine and Rotenone emerged as the most active compounds of the series against cancer cells, also showing good selectivity over normal cells. Notably, the anticancer activity correlated well with the ability of the two compounds to target telomeric G4s.

scholarly journals Identification of effective anticancer G-quadruplex-targeting chemotypes through the exploration of a high diversity library of natural compounds

2021 ◽  
Author(s):  
Mattia Mori ◽  
Chiara Platella ◽  
Francesca Ghirga ◽  
Pasquale Zizza ◽  
Luca Pompili ◽  
...  
Keyword(s):  
Natural Compounds ◽  
G Quadruplex ◽  
High Diversity

scholarly journals The structural plasticity of nucleic acid duplexes revealed by WAXS and MD

2021 ◽  
Vol 7 (17) ◽  
pp. eabf6106
Author(s):  
Weiwei He ◽  
Yen-Lin Chen ◽  
Lois Pollack ◽  
Serdal Kirmizialtin
Keyword(s):  
Structural Diversity ◽  
Conformational Ensemble ◽  
Structural Variations ◽  
Dna And Rna ◽  
X Ray Scattering ◽  
Double Stranded Dna ◽  
Binding Partners ◽  
Rna Duplexes ◽  
Dynamics Simulations ◽  
Integrate Solution

Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.

scholarly journals Isolation and Identification of Actinomycetes Strains from Switzerland and their Biotechnological Potential

2020 ◽  
Vol 74 (5) ◽  
pp. 382-390 ◽  
Author(s):  
Fabienne Arn ◽  
David Frasson ◽  
Ivana Kroslakova ◽  
Fabio Rezzonico ◽  
Joël F. Pothier ◽  
...  
Keyword(s):  
Draft Genome ◽  
Genome Mining ◽  
Bioactive Compound ◽  
Gene Clusters ◽  
Natural Compounds ◽  
Rrna Gene ◽  
Cultivation Conditions ◽  
Screening Assay ◽  
Isolation And Identification ◽  
Bioinformatics Analyses

Actinomycetes strains isolated from different habitats in Switzerland were investigated for production of antibacterial and antitumoral compounds. Based on partial 16S rRNA gene sequences, the isolated strains were identified to genus level. Streptomyces as the largest genus of Actinobacteriawas isolated the most frequently. A screening assay using the OmniLog instrument was established to facilitate the detection of active compounds from actinomycetes. Extracts prepared from the cultivated strains able to inhibit Staphylococcus aureusand Escherichia coliwere further analysed by HPLC and MALDI-TOF MS to identify the produced antibiotics. In this study, the bioactive compound echinomycin was identified from two isolated Streptomycesstrains. Natural compounds similar to TPU-0037-C, azalomycin F4a 2-ethylpentyl ester, a derivative of bafilomycin A1, milbemycin-α8 and dihydropicromycin were detected from different isolated Streptomyces strains. Milbemycin-α8 showed cytotoxic activity against HT-29 colon cancer cells. The rare actinomycete,Micromonospora sp. Stup16_C148 produced a compound that matches with the antibiotic bottromycin A2. The draft genome sequence from Actinokineospora strain B136.1 was determined using Illumina and nanopore-based technologies. The isolated strain was not able to produce antibacterial compounds under standard cultivation conditions. The antiSMASH bioinformatics analyses of the genome from strain B136.1 identified biosynthetic gene clusters with identity values between 4% to 90% to known gene clusters encoding antibiotics. The combinations of cultivation conditions, screening assays, analytical methods and genome mining are important tools to characterize strains of actinomycetes for the identification of their potential to produce natural compounds with antimicrobial activity.

scholarly journals Selective Interactions with Various G-Quadruplex DNA Forming Sequences by Berberine and Palmatine Analogues

2018 ◽  
Author(s):  
Marco Franceschin ◽  
Lorenzo Cianni ◽  
Massimo Pitorri ◽  
Emanuela Micheli ◽  
Stefano Cacchione ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Natural Compounds ◽  
Side Chains ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Quadruplex Formation ◽  
Selective Interactions

In this article/review, the selective interactions of several berberine and palmatine derivatives with various DNA G-quadruplex structures are reported. These derivatives were constructed starting from two natural compounds, berberine and palamatine, through specific synthetic passages following two different schemes for each of them and using several substituents. The details of these synthesis are also described. Indeed, the study of the interactions of these derivative compounds with various G-quadruplex forming sequences was carried out by means of various structural and biochemical techniques. The results show that the presence of suitable side chains are very useful to improve the interaction of the ligands with G-quadruplex structures. Thus, since G-quadruplex formation is promoted by these compounds, which have never been reported before, these may be tested as potential anticancer drugs.

Complete Mitogenome of Threespot Flounder Grammatobothus polyophthalmus (Pleuronectiformes: Bothidae) and Study on the Mechanism of Gene Rearrangement in 13 Bothids

2019 ◽  
Author(s):  
Hairong Luo ◽  
Xiaoyu Kong ◽  
Shixi Chen ◽  
Wei Shi
Keyword(s):  
Gene Rearrangement ◽  
Structural Diversity ◽  
Mitochondrial Genomes ◽  
Gene Rearrangements ◽  
Significant Evidence ◽  
Rearrangement Process ◽  
Genomic Scale ◽  
Complete Mitogenome ◽  
Shed Light ◽  
High Diversity

Abstract Background: The mitochondrial genomes (mitogenomes) of 12 bothids (Pleuronectiformes) from eight genera have been obtained. From the data, the genomic-scale and various gene rearrangements revealed the high diversity of variation in these mitogenomes. Results: A total of 18170 bp of Grammatobothus polyophthalmus mitogenome was determined including 37 genes and two control regions (CRs). Genes encoded by L-strand were grouped to an eight-genes cluster (Q-A-C-Y-S1-ND6-E-P) except for the tRNA-N, other genes encoded by H-strand were grouped together (F-12S … CytB-T) except for the tRNA-D that was translocated to inside of the eight-genes cluster. The mitogenome of G. polyophthalmus and that of 12 known bothids possessed the similar genomic-scale rearrangements with the only differences in the various combinations of CR, tRNA-D and eight-genes cluster, and the shuffling of tRNA-V. Based on the structure character of all 13 bothid mitogenomes, the Dimer-Mitogenome and Non-Random Loss (DMNR) model was fitted to account for all these rearrangements. And the translocation of tRNA-D occurring after the DMNR process in 10 of 13 bothid mitogenomes was confirmed. The striking finding was that each of degenerated genes existing in the gene rearrangement process in 13 bothids had their counterparts of intergenic spaces. Conclusions: The result of corresponding relationship between degenerated genes and intergenic spaces provided the significant evidence to support the possibility of the DMNR model, as well as, the existing of dimeric mitogenome in mitochondrion. The findings of this study were rare phenomenona in teleost fish, which not only promoted the understanding of mitogenome structural diversity, but also shed light on studying of mitochondrial rearrangement and replication.

Nucleoapzymes: catalyst-aptamer conjugates as enzyme-mimicking structures

2019 ◽  
Vol 3 (5) ◽  
pp. 493-499 ◽  
Author(s):  
Verena Wulf ◽  
Itamar Willner
Keyword(s):  
Nucleic Acid ◽  
Variable Structure ◽  
Structural Diversity ◽  
Research Field ◽  
Dynamic Simulations ◽  
Catalytic Function ◽  
Enzyme Mimicking ◽  
G Quadruplex ◽  
Catalytic Sites ◽  
Hydrolysis Of

The conjugation of catalytic sites to sequence-specific, ligand-binding nucleic acid aptamers yields functional catalytic ensembles mimicking the catalytic/binding properties of native enzymes. These catalyst-aptamer conjugates termed ‘nucleoapzymes’ reveal structural diversity, and thus, vary in their catalytic activity, due to the different modes of conjugation of the catalytic units to the nucleic acid aptamer scaffold. The concept of nucleoapzymes is introduced with the assembly of a set of catalysts consisting of the hemin/G-quadruplex DNAzyme (hGQ) conjugated to the dopamine aptamer. The nucleoapzymes catalyze the oxidation of dopamine by H2O2 to yield aminochrome. The catalytic processes are controlled by the structures of the nucleoapzymes, and chiroselective oxidation of l-DOPA and d-DOPA by the nucleoapzymes is demonstrated. In addition, the conjugation of a Fe(III)-terpyridine complex to the dopamine aptamer and of a bis-Zn(II)-pyridyl-salen-type complex to the ATP-aptamer yields hybrid nucleoapzymes (conjugates where the catalytic site is not a biomolecule) that catalyze the oxidation of dopamine to aminochrome by H2O2 and the hydrolysis of ATP to ADP, respectively. Variable, structure-controlled catalytic activities of the different nucleoapzymes are demonstrated. Molecular dynamic simulations are applied to rationalize the structure-catalytic function relationships of the different nucleoapzymes. The challenges and perspectives of the research field are discussed.

scholarly journals The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

2020 ◽  
Vol 21 (6) ◽  
pp. 2017 ◽  
Author(s):  
Stefano Muscat ◽  
Lorenzo Pallante ◽  
Filip Stojceski ◽  
Andrea Danani ◽  
Gianvito Grasso ◽  
...  
Keyword(s):  
Deep Understanding ◽  
Natural Compounds ◽  
Inhibitory Mechanism ◽  
Biophysical Characterization ◽  
Beneficial Effects ◽  
Effective Strategies ◽  
Amyloid Aggregates ◽  
Dynamics Simulations ◽  
Preclinical And Clinical Studies ◽  
The Impact

The pursuit for effective strategies inhibiting the amyloidogenic process in neurodegenerative disorders, such as Alzheimer’s disease (AD), remains one of the main unsolved issues, and only a few drugs have demonstrated to delay the degeneration of the cognitive system. Moreover, most therapies induce severe side effects and are not effective at all stages of the illness. The need to find novel and reliable drugs appears therefore of primary importance. In this context, natural compounds have shown interesting beneficial effects on the onset and progression of neurodegenerative diseases, exhibiting a great inhibitory activity on the formation of amyloid aggregates and proving to be effective in many preclinical and clinical studies. However, their inhibitory mechanism is still unclear. In this work, ensemble docking and molecular dynamics simulations on S-shaped Aβ42 fibrils have been carried out to evaluate the influence of several natural compounds on amyloid conformational behaviour. A deep understanding of the interaction mechanisms between natural compounds and Aβ aggregates may play a key role to pave the way for design, discovery and optimization strategies toward an efficient destabilization of toxic amyloid assemblies.

scholarly journals Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4636 ◽  
Author(s):  
Sabina Podlewska ◽  
Ryszard Bugno ◽  
Lucja Kudla ◽  
Andrzej J. Bojarski ◽  
Ryszard Przewlocki
Keyword(s):  
Molecular Modeling ◽  
G Protein ◽  
Opioid Receptor ◽  
Pearson Correlation ◽  
Interaction Patterns ◽  
Receptor Ligands ◽  
Opioid Receptor Ligands ◽  
Dynamics Simulations

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor.

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