Additional file 2 of Esculetin releases maturation arrest and induces terminal differentiation in leukemic blast cells by altering the Wnt signaling axes

Additional file 2: Supplementary Figure 1. Dynamic induction of early/late phase apoptosis in Kasumi-1 cells upon esculetin treatment : Representative dot plot analysis of esculetin mediated apoptosis based on Annexin V and propidium iodide (PI) staining following 24 and 48h esculetin treatment. Annexin V positive cells were considered to undergo early apoptosis, and Annexin V + PI positive cells as late apoptotic cells. Percentage cell population in each quadrant and relative apoptosis in bar graph (right panel) are combined from three independent experiments. (*p ≤ 0.05; **p ≤ 0.02)

Structure-guided pharmacophore based virtual screening, docking, and molecular dynamics to discover repurposed drugs as novel inhibitors against endoribonuclease Nsp15 of SARS-CoV-2

COVID-19 (Corona Virus Disease of 2019) caused by the novel ‘Severe Acute Respiratory Syndrome Coronavirus-2’ (SARS-CoV-2) has wreaked havoc on human health and the global economy. As a result, for new medication development, it's critical to investigate possible therapeutic targets against the novel virus. ‘Non-structural protein 15’ (Nsp15) endonuclease is one of the crucial targets which helps in the replication of virus and virulence in the host immune system. Here, in the current study, we developed the structure-based pharmacophore model based on Nsp15-UMP interactions and virtually screened several databases against the selected model. To validate the screening process, we docked the top hits obtained after secondary filtering (Lipinski’s rule of five, ADMET & Topkat) followed by 100 ns molecular dynamics (MD) simulations. Next, to revalidate the MD simulation studies, we have calculated the binding free energy of each complex using the MM-PBSA procedure. The discovered repurposed drugs can aid the rational design of novel inhibitors for Nsp15 of the SARS-CoV-2 enzyme and may be considered for immediate drug development. Communicated by Ramaswamy H. Sarma</p

Additional file 1 of Esculetin releases maturation arrest and induces terminal differentiation in leukemic blast cells by altering the Wnt signaling axes

Additional file 1: Supplementary Table 1. Primer sequences used to check expression of individual gene

Additional file 3 of Esculetin releases maturation arrest and induces terminal differentiation in leukemic blast cells by altering the Wnt signaling axes

Additional file 3

ROS is the major player in regulating altered autophagy and lifespan in <i>sin-3</i> mutants of <i>C. elegans</i>

<p>SIN3, a transcriptional corepressor has been implicated in varied functions both as transcription activator and repressor. Recent studies associated Sin3 with the macroautophagic/autophagic process as a negative regulator of Atg8 and Atg32. Though the role of SIN3 in autophagy is being explored, little is known about the overall effect of <i>SIN3</i> deletion on the survival of an organism. In this study using a <i>Caenorhabditis elegans sin-3(tm1279);him-5(e1490)</i> strain, we demonstrate that under <i>in vivo</i> conditions SIN-3 differentially modulates autophagy and lifespan. We provide evidence that the enhanced autophagy and decreased lifespan observed in <i>sin-3</i> deletion mutants is dependent on ROS and intracellular oxidative stress. Inability of the mutant worms to maintain redox balance along with dysregulation of enzymatic antioxidants, depletion of GSH and NADP reserves and elevation of ROS markers compromises the longevity of the worms. It is possible that the enhanced autophagic process observed in <i>sin-3(tm1279);him-5(e1490)</i> worms is required to compensate for oxidative stress generated in these worms.</p> <p><b>Abbreviations:</b><i>cat</i>: catalase; DCFDA: 2ʹ,7ʹ-dichlorodihydrofluoroscein diacetate; GSH: reduced glutathione; GSSG: oxidized glutathione; H₂O₂: hydrogen peroxide; HDAC: Histone deacetylase; HID: HDAC interacting domain; <i>him-5</i>: high incidence of males; HLH-30: Helix Loop Helix-30; HNE: 4-hydroxyl-2-noneal; LIPL: LIPase Like; MDA: malondialdehyde; NGM: nematode growth medium; PAH: paired amphipathic α-helix; PE: phosphatidylethanolamine; RFU: relative fluorescence unit; ROS: reactive oxygen species; <i>sin-3/SIN3</i>: yeast Switch Independent; SOD: superoxide dismutase; NADP: nicotinamide adenine dinucleotide phosphate; SQST-1: SeQueSTosome related-1; ATG: AuTophaGy related</p

Structure-based drug discovery to identify SARS-CoV2 spike protein–ACE2 interaction inhibitors

After the emergence of the COVID-19 pandemic in late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has undergone a dynamic evolution driven by the acquisition of genetic modifications, resulting in several variants that are further classified as variants of interest (VOIs), variants under monitoring (VUM) and variants of concern (VOC) by World Health Organization (WHO). Currently, there are five SARS-CoV-2 VOCs (Alpha, Beta, Delta, Gamma and Omicron), two VOIs (Lambda and Mu) and several other VOIs that have been reported globally. In this study, we report a natural compound, Curcumin, as the potential inhibitor to the interactions between receptor binding domain (RBD(S1)) and human angiotensin-converting enzyme 2 (hACE2) domains and showcased its inhibitory potential for the Delta and Omicron variants through a computational approach by implementing state of the art methods. The study for the first time revealed a higher efficiency of Curcumin, especially for hindering the interaction between RBD(S1) and hACE-2 domains of Delta and Omicron variants as compared to other lead compounds. We investigated that the mutations in the RBD(S1) of VOC especially Delta and Omicron variants affect its structure compared to that of the wild type and other variants and therefore altered its binding to the hACE2 receptor. Molecular docking and molecular dynamics (MD) simulation analyses substantially supported the findings in terms of the stability of the docked complexes. This study offers compelling evidence, warranting a more in-depth exploration into the impact of these alterations on the binding of identified drug molecules with the Spike protein. Further investigation into their potential therapeutic effects in vivo is highly recommended. Communicated by Ramaswamy H. Sarma</p

Semi-quantitative gel picture and Western blot analysis of Heat shock protein70.

(A) represents the semi-quantitative analysis of heat shock protein70 (HSP70) gene and 18S rRNA (Housekeeping gene) in controls and patients respectively.(B) represents the western blots of heat shock protein70 (HSP70) and β-actin protein in controls and patients respectively.</p

Baseline parameters of study subjects.

Baseline parameters of study subjects.</p

Plasma levels of inflammatory markers.

<p>Plasma levels of inflammatory markers.</p

Identification of novel inhibitors of <i>Neisseria gonorrhoeae</i> MurI using homology modeling, structure-based pharmacophore, molecular docking, and molecular dynamics simulation-based approach

MurI is one of the most significant role players in the biosynthesis of the peptidoglycan layer in Neisseria gonorrhoeae (Ng). We attempted to highlight the structural and functional relationship between Ng-MurI and D-glutamate to design novel molecules targeting this interaction. The three-dimensional (3D) model of the protein was constructed by homology modeling and the quality and consistency of generated model were assessed. The binding site of the protein was identified by molecular docking studies and a pharmacophore was identified using the interactions of the control ligand. The structure-based pharmacophore model was validated and employed for high-throughput virtual screening and molecular docking to identify novel Ng-MurI inhibitors. Finally, the model was optimized by molecular dynamics (MD) simulations and the optimized model complex with the substrate glutamate and novel molecules facilitated us to confirm the stability of the protein-ligand docked complexes. The 100 ns MD simulations of the potential lead compounds with protein confirmed that the modeled complexes were stable. This study identifies novel potential compounds with good fitness and docking scores, which made the interactions of biological significance within the protein active site. Hence, the identified compounds may act as new leads to design and develop Ng-MurI inhibitors. Communicated by Ramaswamy H. Sarma</p