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Interleukin 6 (IL-6) is a cytokine with various biological functions in immune regulation, hematopoiesis, and inflammation. Elevated IL-6 levels have been identified in several severe disorders such as sepsis, acute respiratory distress syndrome (ARDS), and most recently, COVID-19. The biological activity of IL-6 relies on interactions with its specific receptor, IL-6Rα, including the membrane-bound IL-6 receptor (mIL-6R) and the soluble IL-6 receptor (sIL-6R). Thus, inhibition of the interaction between these two proteins would be a potential treatment for IL-6 related diseases. To date, no orally available small-molecule drug has been approved. This study focuses on finding potential small molecules that can inhibit protein-protein interactions between IL-6 and its receptor IL-6Rα using its crystal structure (PDB ID: 5FUC). First, two pharmacophore models were constructed based on the interactions between key residues of IL-6 (Phe74, Phe78, Leu178, Arg179, Arg182) and IL-6Rα (Phe229, Tyr230, Glu277, Glu278, Phe279). A database of approximately 22 million compounds was screened using 3D-pharmacophore models, molecular docking models, and ADMET properties. By analyzing the interactive capability of successfully docked compounds with important amino acids, 12 potential ligands were selected for further analysis via molecular dynamics simulations. Based on the stability of the complexes, the high interactions rate of each ligand with the key residues of IL-6/IL-6Rα, and the low binding free energy calculation, two compounds ZINC83804241 and ZINC02997430, were identified as the most potential IL-6 inhibitor candidates. These results will pave the way for the design and optimization of more specific compounds to combat cytokine storm in severe coronavirus patients.

Acetylcholinesterase (AChE) and β-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer’s disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35–85%). Six of the synthetic flavones (B4, B5, B6, B8, D6 and D7) had completely new structures. The AChE and BACE-1 inhibitory activities were tested, giving pIC50 3.47–4.59 (AChE) and 4.15–5.80 (BACE-1). Three compounds (B3, D5 and D6) exhibited the highest biological effects on both AChE and BACE-1. A molecular docking investigation was conducted to explain the experimental results. These molecules could be employed for further studies to discover new structures with dual action on both AChE and BACE-1 that could serve as novel therapies for AD.

Interactions between interleukin (IL)-8 and its receptors, CXCR1, and CXCR2, serve crucial roles in inflammatory conditions and various types of cancers. Inhibition of this signaling pathway has been exploited as a promising strategy in treating these diseases. However, most studies only focused on the design of allosteric antagonists-bound receptors on the intracellular side of IL-8 receptors. Recently, the first cryo-EM structures of IL-8-CXCR2-Gi complexes have been solved, revealing the unique binding and activation modes of the endogenous chemokine IL-8. Hence, we set to identify small molecule inhibitors for IL-8 using critical protein-protein interaction between IL-8 and CXCR2 at the orthosteric binding site. The pharmacophore models and molecular docking screened compounds from DrugBank and NCI databases. The oral bioavailability of the top 23 ligands from the screening was then predicted by the SwissAMDE tool. Molecular dynamics simulation and free binding energy calculation were performed for the best compounds. The result indicated that DB14770, DB12121, and DB03916 could form strong interactions and stable protein-ligand complexes with IL-8. These three candidates are potential IL-8 inhibitors that can be further evaluated by in vitro experiments in the next stage.

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are the two crucial enzymes involved in the pathology of Alzheimer’s disease. The former is responsible for many defects in cholinergic signaling pathway and the latter is the primary enzyme in the biosynthesis of beta-amyloid as the main component of the amyloid plaques. These both abnormalities are found in the brains of Alzheimer’s patients. In this study, in silico models were developed, including 3D-pharmacophore, 2D-QSAR (two-dimensional quantitative structure-activity relationship), and molecular docking, to screen virtually a database of compounds for AChE and BACE-1 inhibitory activities. A combinatorial library containing more than 3 million structures of curcumin and flavonoid derivatives was generated and screened for drug-likeness and enzymatic inhibitory bioactivities against AChE and BACE-1 through the validated in silico models. A total of 47 substances (two curcumins and 45 flavonoids), with remarkable predicted pIC50 values against AChE and BACE-1 ranging from 4.24–5.11 (AChE) and 4.52–10.27 (BACE-1), were designed. The in vitro assays on AChE and BACE-1 were performed and confirmed the in silico results. The study indicated that, by using in silico methods, a series of curcumin and flavonoid structures were generated with promising predicted bioactivities. This would be a helpful foundation for the experimental investigations in the future. Designed compounds which were the most feasible for chemical synthesis could be potential candidates for further research and lead optimization.

The World Health Organization declared monkeypox a global public health emergency on 23 July 2022. This disease was caused by the monkeypox virus (MPXV), which was first identified in 1958 in Denmark. The MPXV is a member of the Poxviridae family, the Chordopoxvirinae subfamily, and the genus Orthopoxvirus, which share high similarities with the vaccinia virus (the virus used to produce the smallpox vaccine). For the initial stage of infection, the MPXV needs to attach to the human cell surface glycosaminoglycan (GAG) adhesion molecules using its E8 protein. However, up until now, neither a structure for the MPXV E8 protein nor a specific cure for the MPXV exists. This study aimed to search for small molecules that inhibit the MPXV E8 protein, using computational approaches. In this study, a high-quality three-dimensional structure of the MPXV E8 protein was retrieved by homology modeling using the AlphaFold deep learning server. Subsequent molecular docking and molecular dynamics simulations (MDs) for a cumulative duration of 2.1 microseconds revealed that ZINC003977803 (Diosmin) and ZINC008215434 (Flavin adenine dinucleotide-FAD) could be potential inhibitors against the E8 protein with the MM/GBSA binding free energies of −38.19 ± 9.69 and −35.59 ± 7.65 kcal·mol−1, respectively.

Background: Nanomaterials have emerged as a transformative approach in modern pharmaceutical applications, offering advanced benefits compared to conventional therapies. Among available pharmaceutical nanomaterials, silver nanoparticles (AgNPs) have been reported with broad-spectrum antimicrobial potential and drug delivery potency. Nevertheless, some studies suggested that chemical synthesis of AgNPs might result in redundant chemicals, posing environmental and health risks. To minimize undesired products, a promising approach is to biologically synthesize this potent nanomaterial. Methods: This study ultilized an eco-friendly system for AgNPs synthesis using Aspergillus terreus isolated from the air. Physical properties of biosynthesized AgNPs were evaluated by UV–visible spectroscopy, dynamic light scattering, and scanning electron microscopy analysis. Antibacterial activity of biosynthesized AgNPs was examined by well diffusion and minimum inhibitory concentration, while in vitro cytotoxicity was used to determine the antitumor activity of AgNPs. Results: The biosynthesized AgNPs had a size of around 60 nm, a PDI inferior to 0.2, and a zeta potential of −30 mV. They exhibited potent antibacterial activity against both Gram-positive and Gram-negative pathogens. Additionally, these nanoparticles also exerted a selective antiproliferative effect on MCF-7, A549, and MDA-MB-231 cell lines. Conclusions: Our research presented the potential of biosynthesized AgNPs using Aspergillus terreus for antimicrobial and anticancer applications, offering an eco-friendly and sustainable alternative to traditional chemical methods.

ABCG2 is an ABC membrane protein reverse transport pump, which removes toxic substances such as medicines out of cells. As a result, drug bioavailability is an unexpected change and negatively influences the ADMET (absorption, distribution, metabolism, excretion, and toxicity), leading to multi-drug resistance (MDR). Currently, in spite of promising studies, screening for ABCG2 inhibitors showed modest results. The aim of this study was to search for small molecules that could inhibit the ABCG2 pump. We first used the WISS MODEL automatic server to build up ABCG2 homology protein from 655 amino acids. Pharmacophore models, which were con-structed based on strong ABCG2 inhibitors (IC50 < 1 μM), consist of two hydrophobic (Hyd) groups, two hydrogen bonding acceptors (Acc2), and an aromatic or conjugated ring (Aro|PiR). Using molecular docking method, 714 substances from the DrugBank and 837 substances from the TCM with potential to inhibit the ABCG2 were obtained. These chemicals maybe favor synthesized or extracted and bioactivity testing.

Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro‐survival acetylation, in all tested animal models but did not always increase K120 and K373/382 acetylation of p53, known as pro‐apoptotic acetylation. HDAC6 ablation induced cellular senescence in primary MEFs and inhibited cell proliferation in HepG2 cells and liver regeneration after two‐thirds partial hepatectomy. However, the genetic ablation of HDAC6 did not inhibit hepatocarcinogenesis, but instead slightly enhanced it in two independent mouse models (DEN + HFD and DEN + TAA). Notably, HDAC6 ablation significantly promoted hepatocarcinogenesis in a multiple DEN treatment hepatocellular carcinoma (HCC) mouse model, mimicking chronic DNA damage in the liver, which correlated with hyperacetylation at K320 of p53 and a decrease in inflammatory cytokines and chemokines. Our data from three independent in vivo animal HCC models emphasize the importance of the complex roles of HDAC6 ablation in hepatocellular carcinogenesis, highlighting its immunosuppressive effects. We provide the first evidence that HDAC6 is a p53 deacetylase at K320, which is especially important for cancer cell survival in chronic DNA damage conditions. Contrary to the general assumption that HDAC6 inhibition leads to hyperacetylation of p53 at K120, resulting in tumor suppression, our findings from in vivo animal HCC modelsemphasize the importance of the opposing roles of HDAC6 ablation in hepatocellular carcinogenesis by highlighting the K320 acetylation of p53 and immunosuppressive effects.

The interleukin-1 receptor like ST2 has emerged as a potential drug discovery target since it was identified as the receptor of the novel cytokine IL-33, which is involved in many inflammatory and autoimmune diseases. For the treatment of such IL-33-related disorders, efforts have been made to discover molecules that can inhibit the protein–protein interactions (PPIs) between IL-33 and ST2, but to date no drug has been approved. Although several anti-ST2 antibodies have entered clinical trials, the exploration of small molecular inhibitors is highly sought-after because of its advantages in terms of oral bioavailability and manufacturing cost. The aim of this study was to discover ST2 receptor inhibitors based on its PPIs with IL-33 in crystal structure (PDB ID: 4KC3) using virtual screening tools with pharmacophore modeling and molecular docking. From an enormous chemical space ZINC, a potential series of compounds has been discovered with stronger binding affinities than the control compound from a previous study. Among them, four compounds strongly interacted with the key residues of the receptor and had a binding free energy <  − 20 kcal/mol. By intensive calculations using data from molecular dynamics simulations, ZINC59514725 was identified as the most potential candidate for ST2 receptor inhibitor in this study.

The fiducial-marks-based alignment process is one of the most critical steps in printed circuit board (PCB) manufacturing. In the alignment process, a machine vision technique is used to detect the fiducial marks and then adjust the position of the vision system in such a way that it is aligned with the PCB. The present study proposed an embedded PCB alignment system, in which a rotation, scale and translation (RST) template-matching algorithm was employed to locate the marks on the PCB surface. The coordinates and angles of the detected marks were then compared with the reference values which were set by users, and the difference between them was used to adjust the position of the vision system accordingly. To improve the positioning accuracy, the angle and location matching process was performed in refinement processes. To overcome the matching time, in the present study we accelerated the rotation matching by eliminating the weak features in the scanning process and converting the normalized cross correlation (NCC) formula to a sum of products. Moreover, the scanning time was reduced by implementing the entire RST process in parallel on threads of a graphics processing unit (GPU) by applying hash functions to find refined positions in the refinement matching process. The experimental results showed that the resulting matching time was around 32× faster than that achieved on a conventional central processing unit (CPU) for a test image size of 1280 × 960 pixels. Furthermore, the precision of the alignment process achieved a considerable result with a tolerance of 36.4 μm.