Structure-guided inhibitor design targeting CntL provides the first chemical validation of the staphylopine metallophore system in bacterial metal acquisition.

To survive in the metal-scarce environment within the host, pathogens synthesize various small molecular metallophores to facilitate the acquisition of transition metals. The cobalt and nickel transporter (Cnt) system synthesizes and transports staphylopine, a nicotianamine-like metallophore, and serves as a primary transition metal uptake system in Gram-positive bacteria including the human pathogen Staphylococcus aureus. In this study, we report the design of the first inhibitor of the Cnt system by targeting the key aminobutanoyltransferase CntL which is involved in the biosynthesis of staphylopine.

Discovery of Novel -Clerodane Derivatives as Potent Dual-Functional Antiosteoporosis Agents through Targeting Peroxisome Proliferator-Activated Receptor-γ.

A library of 31 natural -clerodanes isolated from was assayed for antiosteoporosis. This results in 18 -clerodane osteoclastogenesis inhibitors, and compound prevents bone loss in vivo. Further mechanistic studies demonstrated that these compounds inhibit osteoporosis by antagonizing peroxisome proliferator-activated receptor-γ (PPARγ).

dMXP: A Small-Molecule 3D Structure Predictor with Graph Attention Networks.

Generating the three-dimensional (3D) structure of small molecules is crucial in both structure- and ligand-based drug design. Structure-based drug design needs bioactive conformations of compounds for lead identification and optimization. Ligand-based drug design techniques, such as 3D shape similarity search, 3D pharmacophore model, 3D-QSAR, etc.

Biochemical and structural characterization of chlorhexidine as an ATP-assisted inhibitor against type 1 methionyl-tRNA synthetase from Gram-positive bacteria.

Methionyl-tRNA synthetase (MetRS) catalyzes the attachment of l-methionine (l-Met) to tRNA to generate methionyl-tRNA, an essential substrate for protein translation within ribosome. Owing to its indispensable biological function and the structural discrepancies with human counterpart, bacterial MetRS is considered an ideal target for developing antibacterials. Herein, chlorhexidine (CHX) was identified as a potent binder of Staphylococcus aureus MetRS (SaMetRS) through an ATP-aided affinity screening.

Identification and structural modification of ent-rosane diterpenoids from Euphorbia milii inhibiting RANKL-induced osteoclastogenesis.

Phytochemical study on Euphorbia milii, a common ornamental plant, resulted in the identification of thirteen new ent-rosane diterpenoids (1-13), three new ent-atisane diterpenoids (14-16), and a known ent-rosane (17). Their structures were delineated using spectroscopic data, quantum chemical calculations, and X-ray diffraction experiments. Euphomilone F (1) represented a rare ent-rosane-type diterpenoid with a 5/7/6 skeleton.

Chemical Constituents of Ajuga Lupulina and their Anti-Ferroptosis Activity.

Five new compounds (1, 2, 7, 12, and 16), along with fifteen known ones, were isolated from Ajuga lupulina Maxim. Their structures were revealed by analysing spectroscopic data (MS, NMR), and experimental and calculated ECD spectra was used to deduce the absolute configuration. Compound 16, with eight carbon atoms, was firstly isolated from the nature.

A nomogram for predicting sepsis-associated delirium: a retrospective study in MIMIC III.

Objective: To develop a nomogram for predicting the occurrence of sepsis-associated delirium (SAD).

Materials And Methods: Data from a total of 642 patients were retrieved from the Medical Information Mart for Intensive Care (MIMIC III) database to build a prediction model. Multivariate logistic regression was performed to identify independent predictors and establish a nomogram to predict the occurrence of SAD.

Atractylodinol prevents pulmonary fibrosis through inhibiting TGF-β receptor 1 recycling by stabilizing vimentin.

Pirfenidone and nintedanib are only anti-pulmonary fibrosis (PF) drugs approved by the FDA. However, they are not target specific, and unable to modify the disease status. Therefore, it is still desirable to discover more effective agents against PF.

Discovery of -Clerodane Diterpenoids from as Neuroprotective Agents against Ferroptosis and Neuroinflammation.

Twelve new -clerodane diterpenoids, eight undescribed methoxy/ethoxy acetal analogues, and one new -iridane monoterpenoid were isolated from . Their structures were elucidated using a combination of spectroscopic data, quantum chemical calculations, and X-ray crystallography. This research reveals the distinctive structural features of diterpenes, including distinct C rings and 4,18-double bonds, distinguishing them from diterpenes of other plants in the genus.

Chemical constituents of Ajuga forrestii and their anti-ferroptosis activity.

Six new neoclerodane diterpenoids (1-6), along with ten known compounds (7-16), were isolated from Ajuga forrestii. Their structures were elucidated by HRESIMS, 1D and 2D NMR, ECD calculation, and single-crystal X-ray diffraction analysis. The structure of a known neoclerodane diterpene ajudecunoid C (6) was revised based on the reported NMR empirical rules.

The binding mode of orphan glycyl-tRNA synthetase with tRNA supports the synthetase classification and reveals large domain movements.

As a class of essential enzymes in protein translation, aminoacyl-transfer RNA (tRNA) synthetases (aaRSs) are organized into two classes of 10 enzymes each, based on two conserved active site architectures. The (αβ) glycyl-tRNA synthetase (GlyRS) in many bacteria is an orphan aaRS whose sequence and unprecedented X-shaped structure are distinct from those of all other aaRSs, including many other bacterial and all eukaryotic GlyRSs. Here, we report a cocrystal structure to elucidate how the orphan GlyRS kingdom specifically recognizes its substrate tRNA.

Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors.

Ferroptosis is a new type of cell death associated with many human diseases. It is a new strategy to discover ferroptosis inhibitors for the treatment of ferroptosis-related diseases. Here the FDA-approved drug library containing 1160 molecules was screened for ferroptosis inhibitors in RSL3-induced HT22 mouse hippocampal neuronal cells.

Chemical constituents of industrial hemp roots and their anti-inflammatory activities.

Objective: Although the chemical constituents of the aerial parts of Cannabis have been extensively studied, phytochemicals of Cannabis roots are not well characterized. Herein, we investigated the chemical constituents of industrial hemp (Cannabis sativa L.) roots and evaluated the anti-inflammatory activities of phytochemicals isolated from the hemp roots extract.

Discovery of Spiro[pyrrolidine-3,3'-oxindole] LXRβ Agonists for the Treatment of Osteoporosis.

Osteoclasts have an additional demand for cholesterol compared to normal cells. Liver X receptors (LXRs) are famous for regulation of lipid and cholesterol metabolism. Therefore, we propose that the LXR β agonist can regulate the cholesterol balance in osteoclasts to inhibit osteoclast differentiation.

Discovery and optimization of 2-(trifluoromethyl)benzimidazole derivatives as novel ferroptosis inducers in vitro and in vivo.

Ferroptosis is implicated in diverse human diseases. Ferroptosis inducers hold great potential for cancer therapy. The existing ferroptosis inducers, however, lack structural diversity, and only a few of them are suitable for in vivo applications.

Structure-Guided Design of Halofuginone Derivatives as ATP-Aided Inhibitors Against Bacterial Prolyl-tRNA Synthetase.

Aminoacyl-tRNA synthetases (aaRSs) are promising antimicrobial targets due to their essential roles in protein translation, and expanding their inhibitory mechanisms will provide new opportunities for drug discovery. We report here that halofuginone (HF), an herb-derived medicine, moderately inhibits prolyl-tRNA synthetases (ProRSs) from various pathogenic bacteria. A cocrystal structure of ProRS (ProRS) with HF and an ATP analog was determined, which guided the design of new HF analogs.

Punicesterones A-G, polyhydroxylated mycoecdysteroids from the deep-sea-derived fungus Aspergillus puniceus SCSIO z021.

Seven undescribed polyhydroxylated mycoecdysteroids, punicesterones A-G, along with two known analogues, were isolated from the deep-sea-derived fungal strain Aspergillus puniceus SCSIO z021 (Trichocomaceae). Their structures with absolute configurations were elucidated by a combination of extensive NMR spectroscopic analysis, HRESIMS data, and single-crystal X-ray diffraction experiments. Punicesterone An unexpectedly possessed a nicotinoyl unit substituted at C-22 of a typical ecdysteroid skeleton.

Patient-reported gastrointestinal symptoms following surgery for gastric cancer and the relative risk factors.

Purpose: The study aims to assess the incidence of short-term patient-reported postoperative gastrointestinal symptoms (PGISs) after gastric cancer surgery and explore the relative risk factors for the symptoms.

Methods: Patients with radical gastrectomy were included for this retrospective and observational study. Symptoms extracted from the MD Anderson Symptom Inventory Gastrointestinal Cancer Module (MDASI-GI) were collected in postdischarge week (PDW) 1 and postoperative month (POM) 1.

Identification of a binding site on soluble RANKL that can be targeted to inhibit soluble RANK-RANKL interactions and treat osteoporosis.

One of the major challenges for discovering protein-protein interaction inhibitors is identifying selective and druggable binding sites at the protein surface. Here, we report an approach to identify a small molecular binding site to selectively inhibit the interaction of soluble RANKL and RANK for designing anti-osteoporosis drugs without undesirable immunosuppressive effects. Through molecular dynamic simulations, we discovered a binding site that allows a small molecule to selectively interrupt soluble RANKL-RANK interaction and without interfering with the membrane RANKL-RANK interaction.

Ferroptosis Inhibitory Aromatic Abietane Diterpenoids from and Structural Revision of Two 3,4-Epoxy Group-Containing Abietanes.

Two new 3,4-epoxy group-containing abietane diterpenoids ( and ), together with five known diterpenoids (-), were isolated from . Their structures were elucidated by spectroscopic data analysis, NMR calculations, and X-ray diffraction experiments. The structures of two known abietane diterpenoids were revised based on NMR calculations and X-ray diffraction data.