Design, synthesis, and biological evaluation of 2-substituted-pyridin-4-yl macrocyclic derivatives as new selective HPK1 inhibitors.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor (TCR) signaling and a promising therapeutic target in immunotherapy. Herein, based on the reported HPK1 inhibitor Compound K, a series of 2-substituted-pyridin-4-yl macrocyclic HPK1 inhibitors was designed and synthesized through structure-based drug design and macrocyclization strategies. Detailed SAR studies led to the discovery of compound 2 t, which exhibits excellent HPK1 inhibitory activity (IC = 1.

Identification of natural products targeting human herpesvirus DNA polymerase as antiviral lead.

Infectious herpesviruses are implicated in a broad spectrum of human disorders, from mild cold sores to severe encephalitis and cancers. To combat herpesvirus infections, natural products should be a rich source of potential drug leads. However, natural products have long been bothered by discovering the protein target.

Complementary Fluorescent Probe Pair Targeting Histidinol Dehydrogenase Provides a Useful Tool for Target Validation.

Recent advances in target-based pesticide design have identified numerous novel candidate targets, although their agrochemical potential requires rigorous validation. Fluorescent probes serve as critical tools for tracing molecular interactions and elucidating the target functionality. Herein, we developed a complementary fluorescent probe pair ( and ) to systematically reveal the challenge of targeting histidinol dehydrogenase (HDH) as an agrochemical target.

3D molecular generation models expand chemical space exploration in drug design.

Drug discovery is essential in human diseases but faces challenges because of the vast chemical space. Molecular generation models have become powerful tools to accelerate drug design by efficiently exploring chemical space. 3D molecular generation has gained popularity for explicitly incorporating spatial structural information to generate rational molecules.

Cryo-EM Structures Reveal the Unique Binding Modes of Metyltetraprole in Yeast and Porcine Cytochrome Complex Enabling Rational Design of Inhibitors.

Cytochrome (complex III) represents a significant target for the discovery of both drugs and fungicides. Metyltetraprole (MET) is commonly classified as a quinone site inhibitor (QI) that combats the G143A mutated isolate, which confers high resistance to strobilurin fungicides such as pyraclostrobin (PYR). The binding mode and antiresistance mechanism of MET remain unclear.

AquaticTox: A Web-Based Tool for Aquatic Toxicity Evaluation Based on Ensemble Learning to Facilitate the Screening of Green Chemicals.

The widespread use of chemical products inevitably brings many side effects as environmental pollutants. Toxicological assessment of compounds to aquatic life plays an important role in protecting the environment from their hazards. However, animal testing approaches for aquatic toxicity evaluation are time-consuming, expensive, and ethically limited, especially when there are a great number of compounds.

ACFIS 2.0: an improved web-server for fragment-based drug discovery via a dynamic screening strategy.

Drug discovery, which plays a vital role in maintaining human health, is a persistent challenge. Fragment-based drug discovery (FBDD) is one of the strategies for the discovery of novel candidate compounds. Computational tools in FBDD could help to identify potential drug leads in a cost-efficient and time-saving manner.

Structure-Based Design of 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor as a Potential Herbicide for Cotton Fields.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.

Fragment-based drug discovery supports drugging 'undruggable' protein-protein interactions.

Protein-protein interactions (PPIs) have important roles in various cellular processes, but are commonly described as 'undruggable' therapeutic targets due to their large, flat, featureless interfaces. Fragment-based drug discovery (FBDD) has achieved great success in modulating PPIs, with more than ten compounds in clinical trials. Here, we highlight the progress of FBDD in modulating PPIs for therapeutic development.

Unveiling toxicity profile for food risk components: A manually curated toxicological databank of food-relevant chemicals.

Rigorous risk assessment of chemicals in food and feed is essential to address the growing worldwide concerns about food safety. High-quality toxicological data on food-relevant chemicals are fundamental for risk modeling and assessment in the food safety area. The organization and analysis of substantial toxicity information can positively support decision-making by providing insight into toxicity trends.

Distribution- and Metabolism-Based Drug Discovery: A Potassium-Competitive Acid Blocker as a Proof of Concept.

Conventional methods of drug design require compromise in the form of side effects to achieve sufficient efficacy because targeting drugs to specific organs remains challenging. Thus, new strategies to design organ-specific drugs that induce little toxicity are needed. Based on characteristic tissue niche-mediated drug distribution (TNMDD) and patterns of drug metabolism into specific intermediates, we propose a strategy of distribution- and metabolism-based drug design (DMBDD); through a physicochemical property-driven distribution optimization cooperated with a well-designed metabolism pathway, SH-337, a candidate potassium-competitive acid blocker (P-CAB), was designed.

Exploring the kinase-inhibitor fragment interaction space facilitates the discovery of kinase inhibitor overcoming resistance by mutations.

Protein kinases play crucial roles in many cellular signaling processes, making them become important targets for drug discovery. But drug resistance mediated by mutation puts a barrier to the therapeutic effect of kinase inhibitors. Fragment-based drug discovery has been successfully applied to overcome such resistance.

PTMdyna: exploring the influence of post-translation modifications on protein conformational dynamics.

Protein post-translational modifications (PTM) play vital roles in cellular regulation, modulating functions by driving changes in protein structure and dynamics. Exploring comprehensively the influence of PTM on conformational dynamics can facilitate the understanding of the related biological function and molecular mechanism. Currently, a series of excellent computation tools have been designed to analyze the time-dependent structural properties of proteins.

Web-Based Quantitative Structure-Activity Relationship Resources Facilitate Effective Drug Discovery.

Traditional drug discovery effectively contributes to the treatment of many diseases but is limited by high costs and long cycles. Quantitative structure-activity relationship (QSAR) methods were introduced to evaluate the activity of compounds virtually, which saves the significant cost of determining the activities of the compounds experimentally. Over the past two decades, many web tools for QSAR modeling with various features have been developed to facilitate the usage of QSAR methods.

Fragment-based drug design facilitates selective kinase inhibitor discovery.

Protein kinases (PKs) are important drug targets, but kinases selectivity poses a challenge to protein kinase inhibitors (PKIs) design. Fragment-based drug discovery (FBDD) has achieved great success in the discovery of highly specific PKIs. It makes full use of kinase-fragment interaction in target kinase subpockets to obtain promising selectivity.

Cloud 3D-QSAR: a web tool for the development of quantitative structure-activity relationship models in drug discovery.

Effective drug discovery contributes to the treatment of numerous diseases but is limited by high costs and long cycles. The Quantitative Structure-Activity Relationship (QSAR) method was introduced to evaluate the activity of a large number of compounds virtually, reducing the time and labor costs required for chemical synthesis and experimental determination. Hence, this method increases the efficiency of drug discovery.

Graph attention convolutional neural network model for chemical poisoning of honey bees' prediction.

The impact of pesticides on insect pollinators has caused worldwide concern. Both global bee decline and stopping the use of pesticides may have serious consequences for food security. Automated and accurate prediction of chemical poisoning of honey bees is a challenging task owing to a lack of understanding of chemical toxicity and introspection.

Bioinformatics toolbox for exploring protein phosphorylation network.

A clear systematic delineation of the interactions between phosphorylation sites on substrates and their effector kinases plays a fundamental role in revealing cellular activities, understanding signaling modulation mechanisms and proposing novel hypotheses. The emergence of bioinformatics tools contributes to studying phosphorylation network. Some of them feature the visualization of network, enabling more effective trace of the underlying biological problems in a clear and succinct way.

Monitoring fragmentation and oligomerization of a di-μ-methoxo bridged copper(ii) complex: structure, mass spectrometry, magnetism and DFT studies.

Analyses of the structural information of molecular fragments from the mass spectra of the solid-state products and their reaction solutions allow for the understanding of their formation and of their diverse properties. The reaction of CuCl and (1-methyl-1H-benzo[d]imidazole-2-yl)methanol (HL) led only to crystals containing molecular dimers of [Cu(L)Cl] (Cu2). The Cu-Cu distance and Cu-OR-Cu angle in the structure are 3.

Ferromagnetic coupling in copper benzimidazole chloride: structural, mass spectrometry, magnetism, and DFT studies.

Herein, quasi-square planar Cu(Hmbm)Cl (CBC, Hmbm = (1-methyl-1H-benzo[d]imidazol-2-yl)methanol) was arranged in a pseudo orthogonal way to form Cl-bridged chains, and further ππ interactions resulted in distorted hexagonal layers. DFT calculations reveal a bond strength order of Cu-Cl > Cu-O/N ≫ CuCl. ESI-MS data reveal several small fragments from CBC, but oligomeric [Cu], [Cu], and [Cu] for non-zero in-source energies; MS data indicates the occurrence of several chemical processes, viz.

Hierarchical Assembly and Aggregation-Induced Enhanced Emission of a Pair of Isostructural Zn Clusters.

Information of solid-state and solution structures is crucial in the characterization of molecular clusters and in advancing the understanding of their diverse properties. [EtNH][Zn(hmq)(OH)X] [X = Cl and Br; Hhmq = 2-(hydroxymethyl)quinolin-8-ol] consist of a peanut-shaped ZnO core, in which the Zn atoms occupy the faces and corners of an octahedron and are protected by bonded halogen atoms and bulky organic ligands. Observation of the [Zn(hmq)(OH)X] fragment in electrospray ionization mass spectrometry (ESI-MS) suggests that the cluster is stable in solution.

Effects of tiletamine on the adenosine monophosphate-activated protein kinase signaling pathway in the rat central nervous system.

Objective: The dissociative anesthetic tiletamine, which acts on the central nervous system (CNS), is widely used in veterinary medicine and animal experiments. Recent studies indicate that adenosine 5'-monophosphate activated protein kinase (AMPK) plays a key role in the analgesic action of tiletamine. In the present study, the effects of tiletamine on the AMPK signaling pathway in rats were investigated.

Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy.

Aspirin (ASA) is a cardioprotective drug with anti-cardiac fibrosis action in vivo. This study was aimed to clarify the anti-cardiac fibrosis action of ASA and the underlying mechanisms. Two heart injury models (injection of isoproterenol and ligation of the left anterior descending branch) were used in mice to induce cardiac fibrosis.

Xylazine Activates Adenosine Monophosphate-Activated Protein Kinase Pathway in the Central Nervous System of Rats.

Xylazine is a potent analgesic extensively used in veterinary and animal experimentation. Evidence exists that the analgesic effect can be inhibited using adenosine 5'-monophosphate activated protein kinase (AMPK) inhibitors. Considering this idea, the aim of this study was to investigate whether the AMPK signaling pathway is involved in the central analgesic mechanism of xylazine in the rat.