Efficacy of Oroxylin A in ameliorating renal fibrosis with emphasis on Sirt1 activation and TGF-β/Smad3 pathway modulation.

Introduction: Renal fibrosis poses a serious threat to human health. At present, there are few types of traditional Chinese medicine used to treat this disease, and Oroxylin A (OA), as a natural product with multiple biological activities, is expected to be used for the treatment of renal fibrosis.

Methods: The tolerance of osteoarthritis and its impact on renal fibrosis were studied through ADMET, Lipinski's filter, establishment of a unilateral ureteral obstruction (UUO) model, and molecular docking.

In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and it is highly aggressive and heterogeneous. Targeted therapy is still the main treatment method used in clinic due to its lower risk of side effects and personalized medication. Excessive activation of PI3Kδ in DLBCL leads to abnormal activation of the PI3K/Akt pathway, promoting the occurrence and development of DLBCL.

Copper-Catalyzed Hydrodifluoroalkylation of -benzylacrylamides via Intramolecular 1,4-Hydrogen Atom Transfer: Reaction Development and Mechanistic Insights.

A one-pot protocol for Cu(I)-catalyzed hydrodifluoroalkylation of benzyl-protected acrylamides to construct difluoropentanedioate compounds in moderate to excellent yields has been achieved by using the benzyl group as a traceless redox-active hydrogen donor. The mechanistic studies confirmed that the reaction proceeds by adding a difluoroalkyl radical to acrylamide, followed by unexpected intramolecular 1,4-hydrogen atom transfer (HAT) and SET oxidation reaction. DFT calculations demonstrate that the destabilizing steric repulsion is the key factor controlling the chemoselectivity, which switches from 1,4-HAT to 5- spirocyclization.

Design, synthesis, biological evaluation and molecular dynamics simulation studies of imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B.

Multi-resolution electron spectrometer array for future free-electron laser experiments.

The design of an angular array of electron time-of-flight (eToF) spectrometers is reported, intended for non-invasive spectral, temporal, and polarization characterization of single shots of high-repetition rate, quasi-continuous, short-wavelength free-electron lasers (FELs) such as the LCLS II at SLAC. This array also enables angle-resolved, high-resolution eToF spectroscopy to address a variety of scientific questions on ultrafast and nonlinear light-matter interactions at FELs. The presented device is specifically designed for the time-resolved atomic, molecular and optical science endstation (TMO) at LCLS II.

Exploring Dual Agonists for PPARα/γ Receptors using Pharmacophore Modeling, Docking Analysis and Molecule Dynamics Simulation.

Background: The Peroxisome Proliferator-Activated Receptors (PPARs) are ligandactivated transcription factors belonging to the nuclear receptor family. The roles of PPARα in fatty acid oxidation and PPARγ in adipocyte differentiation and lipid storage have been widely characterized. Compounds with dual PPARα/γ activity have been proposed, combining the benefits of insulin sensitization and lipid lowering into one drug, allowing a single drug to reduce hyperglycemia and hyperlipidemia while preventing the development of cardiovascular complications.

identification of peroxisome proliferator-activated receptor (PPAR)α/γ agonists from Ligand Expo Components database.

PPARα and PPARγ play important roles in regulating glucose and lipid metabolism. In recent years, the development of dual PPAR agonists has become a hot topic in the field of anti-diabetic medicinal chemistry. The dual PPARα/γ agonists can both improve metabolism and reduce side effects caused by single drugs, and has become a promising strategy for designing effective drugs for the treatment of type 2 diabetes.

Virtual identification of novel peroxisome proliferator-activated receptor (PPAR) α/δ dual antagonist by 3D-QSAR, molecule docking, and molecule dynamics simulation.

The therapeutic potential of PPARs antagonists extends beyond diabetes. PPARs antagonists represent a new drug class that holds promise as a broadly applicable therapeutic approach for cancer treatment. Thus, there is a strong need to develop a rational design strategy for creating PPARs antagonists.

Virtual identification of novel PPARα/γ dual agonists by 3D-QSAR, molecule docking and molecular dynamics studies.

Peroxisome proliferator-activated receptors (PPARs) are considered important targets for the treatment of Type 2 diabetes (T2DM). To accelerate the discovery of PPAR α/γ dual agonists, the comparative molecular field analysis (CoMFA) were performed for PPARα and PPARγ, respectively. Based on the molecular alignment, highly predictive CoMFA model for PPARα was obtained with a cross-validated value of 0.

Discovery of novel and highly selective PI3Kδ inhibitors based on the p110δ crystal structure.

Communicated by Ramaswamy H. Sarma.

X-ray mirror surface figure correction with nanometre precision controlled by layer stresses simulated by FEA.

Hard X-rays with energies higher than several kiloelectronvolts can be focused to spot sizes below 10 nm with the present synchrotron beamlines, offering unique advantages for the chemical, elemental and structure analysis of matter. Nevertheless, a surface precision on the nanometre scale for the focusing optics is required and remains the main hurdle limiting X-ray analytical techniques with single-nanometre spatial resolution. On the other hand, to preserve the wavefront properties of coherent X-ray beams, precise control of the reflective mirror surface quality at the nanometre scale is demanded for X-ray free-electron laser applications.

Identification of novel PI3Kδ inhibitors by docking, ADMET prediction and molecular dynamics simulations.

Background: Phosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects.

Method: Computer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database.

Identification of novel PPARα/γ dual agonists by pharmacophore screening, docking analysis, ADMET prediction and molecular dynamics simulations.

PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and cardiac failure. In the recent years, the dual PPARs agonist development has become a hot topic in the antidiabetic medicinal chemistry field.

Synthesis and biological evaluation of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1B.

α-Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity. Therefore, dual antagonists by targeting both α-glucosidase and PTP1B may be potential candidates for type 2 diabetes therapy.

Identification of novel PPARα/γ dual agonists by virtual screening, ADMET prediction and molecular dynamics simulations.

PPARα and PPARγ have been the most widely studied Peroxisome proliferator-activated receptor (PPAR) subtypes due to their important roles in regulating glucose, lipids, and cholesterol metabolism. By combining the lowering serum triglyceride levels benefit of PPARα agonists (such as fibrates) with the glycemic advantages of the PPARγ agonists (such as TZD), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence, has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of virtual screening, ADMET prediction and molecular dynamics (MD) simulations techniques, one compound-ASN15761007 with high binding score, low toxicity were gained.

Finite-element modelling of multilayer X-ray optics.

Multilayer optical elements for hard X-rays are an attractive alternative to crystals whenever high photon flux and moderate energy resolution are required. Prediction of the temperature, strain and stress distribution in the multilayer optics is essential in designing the cooling scheme and optimizing geometrical parameters for multilayer optics. The finite-element analysis (FEA) model of the multilayer optics is a well established tool for doing so.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\pyridine derivatives with the IC50s of 0.49~94.

Synthesis, bioactivity, 3D-QSAR studies of novel dibenzofuran derivatives as PTP-MEG2 inhibitors.

PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM).

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists.

Peroxisome proliferators-activated receptors (PPARα, γ and δ) are potentially effective targets for Type 2 diabetes mellitus therapy. The severe effects of known glitazones and the successfully approved agents (saroglitazar and lobeglitazone) motivated us to study novelly potent PPARs drugs with improved safety profile. In this work, we received 15 carboxylic acids based on the combination principle to integrate the polar head of bezafibrate with the hydrophobic tail of pioglitazone.

Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ by core hopping of telmisartan.

It has been reported previously that some angiotensin II receptor blockers not only antagonize angiotensin II type 1 receptor (ATR), but also exert stimulation in peroxisome proliferator-activated receptor γ (PPARγ) partial activation, among which telmisartan displays the best. Telmisartan has been tested as a bifunctional ligand with antihypertensive and hypoglycemic activity. Aiming at more potent leads with selective ATR antagonism and PPARγ partial agonism, the three parts of telmisartan including the distal benzimidazole ring, the biphenyl moiety, and the carboxylic acid group experienced modification by core hopping method in our study.

Multitargeted bioactive ligands for PPARs discovered in the last decade.

Type 2 diabetes took insulin resistance as the main clinical manifestation. PPARs have been reported to be the therapeutic targets of metabolic disorders, such as obesity, hypertension, diabetes, and cardiovascular disease. Previously, PPARγ agonist rosiglitazone was restricted in clinic due to cardiomyocytes infarction, weight gain, and other serious side-effects, which were mainly due to the single and selective PPARγ agonism.

Identification of Novel PPARα/γ Dual Agonists by Virtual Screening of Specs Database.

Rosiglitazone was restricted clinically due to the side effects such as edema, weight gain and cardiac failure mainly attributing to the single and selective PPARγ activation. Nowadays, multi-targeted PPARs agonists remained to be a hot topic in the antidiabetic medicinal chemistry field. In this paper, the cooperative PPARα/γ dual agonists were screened from Specs database via the flow chart of docking, ADMET prediction and molecular dynamics (MD) simulations.

Synthesis, biological evaluation and 3D-QSAR studies of imidazolidine-2,4-dione derivatives as novel protein tyrosine phosphatase 1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) plays a vital role in the regulation of insulin sensitivity and dephosphorylation of the insulin receptor, so PTP1B inhibitors may be potential agents to treat type 2 diabetes. In this work, a series of novel imidazolidine-2,4-dione derivatives were designed, synthesized and assayed for their PTP1B inhibitory activities. These compounds exhibited potent activities with IC50 values at 0.

Thermal stress prediction in mirror and multilayer coatings.

Multilayer optics for X-rays typically consist of hundreds of periods of two types of alternating sub-layers which are coated on a silicon substrate. The thickness of the coating is well below 1 µm (tens or hundreds of nanometers). The high aspect ratio (∼10(7)) between the size of the optics and the thickness of the multilayer can lead to a huge number of elements (∼10(16)) for the numerical simulation (by finite-element analysis using ANSYS code).