Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform.

COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, , that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5.

Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.

Metallo-β-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic β-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates.

Metal binding pharmacophore click-derived discovery of new broad-spectrum metallo-β-lactamase inhibitors.

The emergence of metallo-β-lactamases (MBLs) confers resistance to nearly all the β-lactam antibiotics, including carbapenems. Currently, there is a lack of clinically useful MBL inhibitors, making it crucial to discover new inhibitor chemotypes that can potently target multiple clinically relevant MBLs. Herein we report a strategy that utilizes a metal binding pharmacophore (MBP) click approach to identify new broad-spectrum MBL inhibitors.

New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies.

SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions.

Metallo-β-lactamase-mediated antimicrobial resistance and progress in inhibitor discovery.

Resistance to β-lactam antibiotics is rapidly growing, substantially due to the spread of serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs), which efficiently catalyse β-lactam hydrolysis. Combinations of a β-lactam antibiotic with an SBL inhibitor have been clinically successful; however, no MBL inhibitors have been developed for clinical use. MBLs are a worrying resistance vector because they catalyse hydrolysis of all β-lactam antibiotic classes, except the monobactams, and they are being disseminated across many bacterial species worldwide.

Design, Synthesis, and Biological Evaluation of New 1H-Imidazole-2-Carboxylic Acid Derivatives as Metallo-β-Lactamase Inhibitors.

As one of important mechanisms to β-lactam antimicrobial resistance, metallo-β-lactamases (MBLs) have been receiving increasing worldwide attentions. Ambler subclass B1 MBLs are most clinically relevant, because they can hydrolyze almost all β-lactams with the exception of monobactams. However, it is still lacking of clinically useful drugs to combat MBL-medicated resistance.

[Composition changes reveal relationship between color and enzymatic reaction of Magnoliae Officinalis Cortex during "sweating" process].

In this study, we employed Q Exactive to determine the main differential metabolites of Magnoliae Officinalis Cortex du-ring the "sweating" process. Further, we quantified the color parameters and determined the activities of polyphenol oxidase(PPO), peroxidase(POD), and tyrosinase of Magnoliae Officinalis Cortex during the "sweating" process. Gray correlation analysis was performed for the color, chemical composition, and enzyme activity to reveal the effect of enzymatic reaction on the color of Magnoliae Officinalis Cortex during the "sweating" process.

Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors.

Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the 'last-resort' carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria.

Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates.

Human sirtuin 5 (SIRT5) plays pivotal roles in metabolic pathways and other biological processes, and is involved in several human diseases including cancer. Development of new potent and selective SIRT5 inhibitors is currently desirable to provide potential therapeutics for related diseases. Herein, we report a series of new 3-thioureidopropanoic acid derivatives, which were designed to mimic the binding features of SIRT5 glutaryl-lysine substrates.

ProfKin: A comprehensive web server for structure-based kinase profiling.

Protein kinases are central mediators of signal-transduction cascades and attractive drug targets for therapeutic intervention. Since kinases are structurally and mechanistically related to each other, kinase inhibitor selectivity is often investigated by kinase profiling and considered as an important index for drug discovery. We here describe a versatile web server termed ProfKin for structure-based kinase profiling, which is based on a kinase-ligand focused database (KinLigDB).

Design and enantioselective synthesis of 3-(α-acrylic acid) benzoxaboroles to combat carbapenemase resistance.

Chiral 3-substituted benzoxaboroles were designed as carbapenemase inhibitors and efficiently synthesised via asymmetric Morita-Baylis-Hillman reaction. Some of the benzoxaboroles were potent inhibitors of clinically relevant carbapenemases and restored the activity of meropenem in bacteria harbouring these enzymes. Crystallographic analyses validate the proposed mechanism of binding to carbapenemases, i.

Discovery of 3-aryl substituted benzoxaboroles as broad-spectrum inhibitors of serine- and metallo-β-lactamases.

The production of β-lactamases represents the main cause of resistance to clinically important β-lactam antibiotics. Boron containing compounds have been demonstrated as promising broad-spectrum β-lactamase inhibitors to combat β-lactam resistance. Here we report a series of 3-aryl substituted benzoxaborole derivatives, which manifested broad-spectrum inhibition to representative serine-β-lactamases (SBLs) and metallo-β-lactamases (MBLs).

[Active components and mechanism of Taohong Siwu Decoction in treatment of primary dysmenorrhea based on network pharmacology and molecular docking technology].

This paper aimed to investigate the active components and mechanism of Taohong Siwu Decoction in the treatment of primary dysmenorrhea(PD) based on network pharmacology and molecular docking technology. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) was used to search the chemical compositions and targets of six herbs in Taohong Siwu Decoction. The targets for PD treatment were selected through the databases of DrugBank, OMIM, TTD and CTD, and gene annotation of the targets was conducted with UniProt database.

[Comparative transcriptome and proteome profiling of chlorophyll metabolism pathway in four types of Magnolia officinalis].

Magnolia officinalis is a traditional Chinese medicine,with many years of cultivating process, M. officinalis leaves show more differentiation types due to the exchange of seeds from different provenances. "Da Ao"(DA), "Xiao Ao"(XA), "Chuan Hou"(CH),and "Liu Ye"(LY)are the main types of M.

Discovery of mercaptopropanamide-substituted aryl tetrazoles as new broad-spectrum metallo-β-lactamase inhibitors.

β-Lactam antibiotic resistance mediated by metallo-β-lactamases (MBL) has threatened global public health. There are currently no available inhibitors of MBLs for clinical use. We previously reported the ruthenium-catalyzed meta-selective C-H nitration synthesis method, leading to some -mercaptopropanamide substituted aryl tetrazoles as new potent MBL inhibitors.

Sensitive fluorogenic substrates for sirtuin deacylase inhibitor discovery.

Sirtuins (SIRTs) are NAD-dependent lysine deacylases, regulating many important biological processes such as metabolism and stress responses. SIRT inhibitors may provide potential benefits against SIRT-driven human diseases. Development of efficient assay platforms based on fluorogenic substrates will facilitate the discovery of high-quality SIRT inhibitors.

Principles and current strategies targeting metallo-β-lactamase mediated antibacterial resistance.

Resistance to β-lactam antibacterials is commonly associated with the production of the serine β-lactamases (SBLs) and/or metallo-β-lactamases (MBLs). Although clinically useful inhibitors for the SBLs have been developed, no equivalent inhibitors are available for the MBLs, which can hydrolyze almost all β-lactam antibiotics, including the so-called "last resort" carbapenems. It is still a challenging task to develop a clinically useful inhibitor that should be broad-spectrum targeting multiple clinically relevant MBL enzymes that differ in their active site features.

MeLAD: an integrated resource for metalloenzyme-ligand associations.

Motivation: Metalloenzymes are attractive targets for therapeutic intervention owing to their central roles in various biological processes and pathological situations. The fast-growing body of structural data on metalloenzyme-ligand interactions is facilitating efficient drug discovery targeting metalloenzymes. However, there remains a shortage of specific databases that can provide centralized, interconnected information exclusive to metalloenzyme-ligand associations.

Structure-Based Development of (1-(3'-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-β-lactamases.

The emergence and spread of bacterial pathogens acquired metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) medicated β-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2')-(1-(3'-mercapto-2'-methylpropanamido)methyl)boronic acid () as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2: and KPC-2: complex structures, further structural optimization yielded new, more potent dual-action inhibitors.

Crystallographic and SAR analyses reveal the high requirements needed to selectively and potently inhibit SIRT2 deacetylase and decanoylase.

A high-quality X-ray crystal structure reveals the mechanism of compound inhibiting SIRT2 deacetylase and decanoylase. Structure-activity relationship (SAR) analysis of the synthesized derivatives of reveals the high requirements needed for selective inhibitors to bind with the induced hydrophobic pocket and potently inhibit sirtuin 2 deacetylase.

[Dynamic response and variance of vegetation in China from 1982 to 2015 under the asymmetric rate of temperature fluctuation.].

The impact of global warming on the growth and development of natural vegetation is an important concern worldwide. Based on the data from the vegetation normalization index, daytime temperature (T), nighttime temperature (T), precipitation, and elevation from 1982 to 2015, we examined the day-night warming response of 42 types of natural vegetation in China. The results showed that both the temperature at day and night was significantly increased in the study area, with obvious asymmetry.

[Pollution Characteristics and Health Risk Assessment of Heavy Metals in Wheat Grains Cultivated in Kaifeng Irrigation Area of the Yellow River].

In order to monitor heavy metal pollution in agricultural soils and assess the corresponding health risk in the Yellow River irrigation area, this study applied the Nemero index and the health risk index to evaluate heavy metal pollution in wheat grains and the health risks for residents in the lower reaches of the Yellow River. Four towns in Kaifeng, which are within the lower reaches of the Yellow River, were selected as the study area. The examination of wheat samples revealed that the average contents of Cd, Cr, Pb, Cu, Zn, Ni, and Hg in the wheat grains were 0.

X-ray crystal structure guided discovery of new selective, substrate-mimicking sirtuin 2 inhibitors that exhibit activities against non-small cell lung cancer cells.

Human sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD)-dependent deacylase, and is implicated in human diseases including cancer. Selective small-molecule inhibitors for SIRT2 are sought as chemical tools and potential therapeutics. Here we report the X-ray crystal structure guided structure-activity relationship studies of new N-(3-(phenoxymethyl)phenyl)acetamide derivatives with SIRT2, which led to the identification of potent, selective SIRT2 inhibitors.