Objective: The study aimed to investigate candidate circular RNAs (circRNAs) in regulating the pathogenic process of esophageal carcinoma. Methods: Specimens were collected from the patients with esophageal carcinoma. Total RNA was purified and treated with RNase R followed by RNA-seq in the purpose of screening the circRNAs in significant differentially expression. The expression level of the screened circRNAs were further validated using RT-PCR. The circular structure of the circRNA was validated with divergent and convergent primers. Overexpression vector was prepared in the purpose of raising the expression level of circ0043898 in the ECA-109 and Kyse-520 cells. The cell colony assay and MTS assay were conducted to determine the capacity of cell proliferation. Chamber assays were applied to determine the capacity of cell migration and invasion while flowcytometry was applied to determine the cell cycle and cell apoptosis. In vivo animal assay was conducted by injecting the cells to the chest of the mice. RNA-seq was performed followed by GO and KEGG study to further verify the regulation mechanism of circ0043898. Results: circ0043898 was validated that down-regulated expressed in the specimens from the patients with esophageal carcinoma. The cell assays proved that overexpression of circ0043898 can obviously inhibit the cell proliferation, cell migration and invasion and induce cell apoptosis and death in the cancerous cells. The in vivo animal study also suggested that the circ0043898 performed inhibitory functions on oncogenesis. The RNA-seq presented the potential regulation mechanism of circ0043898. Histone H3 and BMI1 were presented significantly differential expression in both ECA-109 and Kyse-520 cells, indicating they might be the targets of circ0043898. Conclusion: circ0043898 is presented as tumor inhibitor and could be a candidate biomarker in the therapeutic target and diagnosis of esophageal carcinoma.
Human glutaminyl cyclase (hQC) appeared as a promising new target with its inhibitors attracted much attention for the treatment of Alzheimer's disease (AD) in recent years. But so far, only a few compounds have been reported as hQC inhibitors. To find novel and potent hQC inhibitors, a high-specificity ZBG (zinc-binding groups)-based pharmacophore model comprising customized ZBG feature was first generated using HipHop algorithm in Discovery Studio software for screening out hQC inhibitors from the SPECS database. After purification by docking studies and drug-like ADMET properties filters, four potential hit compounds were retrieved. Subsequently, these hit compounds were subjected to 30-ns molecular dynamic (MD) simulations to explore their binding modes at the active side of hQC. MD simulations demonstrated that these hit compounds formed a chelating interaction with the zinc ion, which was consistent with the finding that the electrostatic interaction was the major driving force for binding to hQC confirmed with MMPBSA energy decomposition. Higher binding affinities of these compounds were also verified by the binding free energy calculations comparing with the references. Thus, these identified compounds might be potential hQC candidates and could be used for further investigation.
Recently, the development of Src/Abl (c-Src/Bcr-Abl tyrosine kinases) dual inhibitors has attracted considerable attention from the research community for treatment of malignancies. In order to explore the different structural features impacting the Src and Abl inhibitory activities of N(9)-arenethenyl purines and to investigate the molecular mechanisms of ligand-receptor interactions, a molecular modeling study combining the three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations was performed. The obtained CoMFA (comparative molecular field analysis) models exhibited satisfactory internal and external predictability. The plots of the CoMFA fields could be used to investigate the structural differences between DFG-in (targeting the active enzyme conformation) and DFG-out (targeting the inactive enzyme conformation) inhibitors. The key amino acid residues were identified by docking studies, and the detailed binding modes of the compounds with different activities were determined by MD simulations. The binding free energies gave a good correlation with the experimental determined activities. In an energetic analysis, the MM-PBSA (molecular mechanics Poisson-Boltzmann surface) energy decomposition revealed that the van der Waals interactions were the major driving force for the binding of the DFG-in and DFG-out compounds to Src and Abl, especially the hydrophobic interactions between ligands and residues Ala403/380, Asp404/381, and Phe405/382 in DFG-out Src and Abl complexes. They also help to stabilize the DFG-out conformations. These results can offer useful references for designing novel potential DFG-in and DFG-out dual Src/Abl inhibitors.
P2Y receptor is an attractive target for the anti-platelet therapies, treating various thrombotic diseases. In this work, a total of 107 6-aminonicotinate-based compounds as potent P2Y antagonists were studies by a molecular modeling study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations to explore the decisive binding conformations of these antagonists with P2Y and the structural features for the activity. The optimum CoMFA and CoMSIA models identified satisfactory robustness and good predictive ability, with R = .983, q = .805, [Formula: see text] = .881 for CoMFA model, and R = .935, q = .762, [Formula: see text] = .690 for CoMSIA model, respectively. The probable binding modes of compounds and key amino acid residues were revealed by molecular docking. MD simulations and MM/GBSA free energy calculations were further performed to validate the rationality of docking results and to compare the binding modes of several compound pairs with different activities, and the key residues (Val102, Tyr105, Tyr109, His187, Val190, Asn191, Phe252, His253, Arg256, Tyr259, Thr260, Val279, and Lys280) for the higher activity were pointed out. The binding energy decomposition indicated that the hydrophobic and hydrogen bond interactions play important roles for the binding of compounds to P2Y. We hope these results could be helpful in design of potent and selective P2Y antagonists.
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