Cytotoxic and apoptotic effects of some (R)-carvone-isoxazoline derivatives on human fibrosarcoma and carcinoma cells: experimental evaluation for cytotoxicity, molecular docking and molecular dynamics studies.

This study aimed to analyze the cytotoxic and apoptotic effects of isoxazoline derivatives with monoterpene scaffold 9a-e in HT-1080 fibrosarcoma, MCF-7, and MDA-MB-231 breast carcinoma, and A-549 lung carcinoma. The cytotoxic effects data revealed that compounds 9a-e generally induced significant cell growth inhibition in all cell lines, with IC50 ranging from 10 to 30 µM. However, for compounds 9c and 9e, the IC50 reached a value of 100 µM in HT-1080 cells. Compounds 9a, 9b, and 9d could induce apoptosis in HT-1080 cells as demonstrated by Annexin-V labeling and Caspase-3/7 activity. The apoptotic effect was accompanied by cell cycle arrest in the S phase. Molecular docking and molecular dynamics confirmed the empirical assay results and confirmed the stability of the complex with the inhibition of the anti-apoptotic protein, leading to cancer cell death. Overall, these data suggest that the proposed isoxazoline derivatives may be potential candidates for further investigation to evaluate their efficacy and optimal use in cancer treatment.Communicated by Ramaswamy H. Sarma.

In silico discovery of novel inhibitors from Northern African natural products database against main protease (Mpro) of SARS-CoV-2.

The recent outbreak of COVID-19 (Coronavirus Disease 2019), caused by a novel SARS-CoV-2 virus, has led to public health emergencies worldwide where time is as important as equipment to save lives. Antimalarial drugs such as hydroxychloroquine and chloroquine derivatives are used in emergencies but they are not suitable for patients with high blood pressure, diabetes and heart problems. Since there are no approved drugs for this disease, science is challenged to find vaccines and new drugs. Therefore, as part of our Silico drug design strategy, we identified drug-like compounds that inhibit replication of the main protease (Mpro) of SARS-CoV-2 based on receptor-based virtual database screening, molecular docking, molecular dynamics, and drug-similarity profiling from the NANPDB natural products database available at North African. The two resulting hit compounds named 5- Chloro-Omega-hydroxy-1-O-methylemodin and cystodion E showed the highest binding energy with Mpro of SARS-CoV-2 and strong inhibitory activity compared with the previously published N3 inhibitor. The complexes of these two compounds were validated by molecular dynamics analysis (RMSD, RMSF, Rg, total number of hydrogen bonds and secondary structure fractions of the protein in the complex) as the best method to evaluate the biological stability of the system. Therefore, these molecules deserve more attention in drug development compared to COVID-19. HighlightsA large database of natural compounds was screened against nCoV-2's Mpro.Molecular docking and Molecular dynamics were used as powerful methods.Two compounds were found are very attractive to inhibit Mpro of nCoV-2.ADME-Tox profiling is evaluated the active compounds are not cancerogenic.Communicated by Ramaswamy H. Sarma.

Binding-Induced Diversity of a Human Telomeric G-Quadruplex Stability Phase Space.

The structural polymorphism of G-quadruplex nucleic acids is an important factor in their recognition by proteins and small-molecule ligands. However, it is not clear why the binding of several ligands alters G-quadruplex topology. We addressed this question by following the (un)folding and binding of the human telomeric fragment 5'-(GGGTTA)3GGGT-3' (22GT) by calorimetry (DSC, ITC) and spectroscopy (CD). A thermodynamic analysis of the obtained data led to a detailed description of the topological phase space of stability (phase diagram) of 22GT and shows how it changes in the presence of a specific bisquinolinium ligand (360A). Various 1:1 and 2:1 ligand-quadruplex complexes were observed. With increasing temperature, the 1:1 complexes transformed into 2:1 complexes, which is attributed to the preferential binding of the ligand to the folding intermediates. Overall, the dissection of the thermodynamic parameters in combination with molecular modelling clarified the driving forces of the topological quadruplex transformations in a wide range of ligand concentrations and temperatures.

Inhibition of the SARS-CoV-2 3CLpro main protease by plant polyphenols.

The abundance of polyphenols in edible plants makes them an important component of human nutrition. Considering the ongoing COVID-19 pandemic, a number of studies have investigated polyphenols as bioactive constituents. We applied in-silico molecular docking as well as molecular dynamics supported by in-vitro assays to determine the inhibitory potential of various plant polyphenols against an important SARS-CoV-2 therapeutic target, the protease 3CLpro. Of the polyphenols in initial in-vitro screening, quercetin, ellagic acid, curcumin, epigallocatechin gallate and resveratrol showed IC50 values of 11.8 µM to 23.4 µM. In-silico molecular dynamics simulations indicated stable interactions with the 3CLpro active site over 100 ns production runs. Moreover, surface plasmon resonance spectroscopy was used to measure the binding of polyphenols to 3CLpro in real time. Therefore, we provide evidence for inhibition of SARS-CoV-2 3CLpro by natural plant polyphenols, and suggest further research into the development of these novel 3CLpro inhibitors or biochemical probes.

Energetic Basis of AGCGA-Rich DNA Folding into a Tetrahelical Structure.

It was recently discovered that, besides well-known G-quadruplexes and i-motifs, DNA may adopt another type of noncanonical structure called AGCGA-quadruplexes. Here, the folding of the VK2 fragment from the regulatory region of the PLEKHG3 gene is studied and, for the first time, the energetic contributions that stabilize this unique fold are described. Similarly to the B-DNA, it is stabilized by hydrophobic desolvation and, in contrast to G-quadruplexes, also by specific binding of water molecules. Compared to B-DNA, VK2 folding is enthalpically less favorable due to poorer base-stacking interactions, resulting in substantial conformational flexibility. This entropically favorable conformational "breathing" stabilizes the AGCGA-quadruplexes. In conclusion, AGCGA-quadruplexes have a distinguishing thermodynamic fingerprint and the corresponding driving forces enabling their folding are consistent with the observed structural features.