Assembly and architecture of endogenous NMDA receptors in adult cerebral cortex and hippocampus.

The cerebral cortex and hippocampus are crucial brain regions for learning and memory, which depend on activity-induced synaptic plasticity involving N-methyl-ᴅ-aspartate receptors (NMDARs). However, subunit assembly and molecular architecture of endogenous NMDARs (eNMDARs) in the brain remain elusive. Using conformation- and subunit-dependent antibodies, we purified eNMDARs from adult rat cerebral cortex and hippocampus.

Structure-Based Rational Design and Evaluation of BET-Aurora Kinase Dual-Inhibitors for Treatment of Cancers.

Simultaneous inhibition of the bromodomain and extra-terminal domain and Aurora kinases is a promising anticancer therapeutic strategy. Based on our previous study on BET-kinase dual inhibitors, we employed the molecular docking approach to design novel dual BET-Aurora kinase A inhibitors. Through several rounds of optimization and with the guidance of the solved cocrystal structure of BRD4 bound to inhibitor , we finally obtained a series of highly potent dual BET-Aurora kinase A inhibitors.

Inhibition of cap-dependent endonuclease in influenza virus with ADC189: a pre-clinical analysis and phase I trial.

ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts.

Current advances on the phytochemistry, pharmacology, quality control and applications of .

(Wall.) Lindl. (AR) is a perennial herb that has long been used as medicinal and edible plant.

Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery.

G protein-coupled receptors (GPCRs) adopt conformational states that activate or inhibit distinct signaling pathways, including those mediated by G proteins or β-arrestins. Biased signaling through GPCRs may offer a promising strategy to enhance therapeutic efficacy while reducing adverse effects. Cannabinoid receptor 1 (CB1), a key GPCR in the endocannabinoid system, presents therapeutic potential for conditions such as pain, anxiety, cognitive impairment, psychiatric disorders, and metabolic diseases.

C-diterpenoid alkaloids isolated from Delphinium forrestii var. viride.

Delphinium forrestii var. viride is a plant of the genus Delphinium in the family Ranunculaceae. The chemical composition of the 95% ethanol extract of the whole herb of D.

OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.

Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210).

Design, synthesis, and evaluation of the pharmacological activity of novel NMDA receptor antagonists based on the germacrone scaffold.

The NMDA receptor has long attracted researchers' attention due to its potential as a drug target and its central role in the central nervous system. The NMDA receptor is a ligand-gated and voltage-dependent ion channel widely distributed in the central nervous system. In this study, we employed a drug design strategy combining "molecular assembly" and "combinatorial chemistry.

Proteomics: An In-Depth Review on Recent Technical Advances and Their Applications in Biomedicine.

Proteins hold pivotal importance since many diseases manifest changes in protein activity. Proteomics techniques provide a comprehensive exploration of protein structure, abundance, and function in biological samples, enabling the holistic characterization of overall changes in organisms. Nowadays, the breadth of emerging methodologies in proteomics is unprecedentedly vast, with constant optimization of technologies in sample processing, data collection, data analysis, and its scope of application is steadily transitioning from the bench to the clinic.

Design, synthesis and biological evaluation of novel 1H-indole-3-carbonitrile derivatives as potent TRK Inhibitors.

Tropomyosin receptor kinase (TRK) has emerged as a promising therapeutic target in cancers driven by NTRK gene fusions. Herein, we report a highly potent TRK inhibitor, C11, developed using bioisosteric replacement and computer-aided drug design (CADD) strategies. Compound C11 demonstrated significant antiproliferative effects against TRK-dependent cell lines (Km-12), and exhibited a dose-dependent inhibition of both colony formation and cell migration.

Selectivity mechanism of inhibition towards Phosphodiesterase 1B and phosphodiesterase 10A in silico investigation.

Due to the unclear selectivity of the protein system, designing selective small molecule inhibitors has been a significant challenge. This issue is particularly prominent in the phosphodiesterases (PDEs) system. Phosphodiesterase 1B (PDE1B) and phosphodiesterase 10 A (PDE10A) are two closely related subtypes of PDE proteins that play diverse roles in the immune system and tumorigenesis, respectively.

Correction: Zhang et al. GL-1196 Suppresses the Proliferation and Invasion of Gastric Cancer Cells via Targeting PAK4 and Inhibiting PAK4-Mediated Signaling Pathways. 2016, , 470.

In the original publication [...

Targeting cryptic allosteric sites of G protein-coupled receptors as a novel strategy for biased drug discovery.

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are highly effective targets for therapeutic drugs. GPCRs couple different downstream effectors, including G proteins (such as Gi/o, Gs, G12, and Gq) and β-arrestins (such as β-arrestin 1 and β-arrestin 2) to mediate diverse cellular and physiological responses. Biased signaling allows for the specific activation of certain pathways from the full range of receptors' signaling capabilities.

Lanosterol 14α-Demethylase (CYP51)/Heat Shock Protein 90 (Hsp90) Dual Inhibitors for the Treatment of Invasive Candidiasis.

Invasive candidiasis has attracted global attention with a high incidence and mortality. Current antifungal drugs are limited by unfavorable therapeutic efficacy, significant hepatorenal toxicity, and the development of drug resistance. Herein, we designed the first generation of lanosterol 14α-demethylase (CYP51)/heat shock protein 90 (Hsp90) dual inhibitors on the basis of antifungal synergism.

Design, synthesis and activity evaluation of reduction-responsive anticancer peptide temporin-1CEa drug conjugates.

Membranes that destroy anticancer peptides can bind to negatively charged cancer cell membranes through electrostatic interactions, destroying their functions and leading to cancer cell necrosis. Temporin-1CEa, obtained from the skin secretions of the Chinese frog Rana chensinensis, is an anticancer peptide with 17 amino acid residues that exhibits concentration-dependent cytotoxicity against a variety of cancer cell lines, although it has no obvious cytotoxicity to normal HUVECs. In this work, we designed and synthesized 12 derivative peptides through double-cysteine scanning of temporin-1CEa-truncated peptides.

Tamsulosin ameliorates bone loss by inhibiting the release of Cl through wedging into an allosteric site of TMEM16A.

TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.

Structure-Based Design of 2-Aminopyrazolpyrimidopyridone Derivatives as New Rearranged During Transfection (RET) Kinase Inhibitors.

RET (Rearranged during transfection) kinase is a validated target for non-small cell lung cancer (NSCLC). In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by the US FDA. However, high treatment costs and clinically acquired resistance (e.

Advances in structure-based allosteric drug design.

The identification of allosteric binding sites forms a critical connection between structural and computational biology, substantially advancing the discovery of allosteric drugs. However, the prevailing strategies for allosteric drug development predominantly rely on high-throughput screening, which suffers from high failure rates due to a limited understanding of allosteric mechanisms. This review collects insights from case studies on allosteric mechanisms, protein structure databases and computation algorithm developments, aiming to enhance our comprehension of allostery and guide more effective allosteric drug development.

Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.

Macrocyclization is a compelling strategy for conventional drug design for improving biological activity, target specificity, and metabolic stability, but it was rarely applied to the design of PROTACs possibly due to the mechanism and structural complexity. Herein, we report the rational design of the first series of "Head-to-Tail" macrocyclic PROTACs. The resulting molecule exhibited pronounced Brd4 protein degradation with low nM DC values while almost totally dismissing the "hook effect", which is a general character and common concern of a PROTAC, in multiple cancer cell lines.

Design, synthesis and biological evaluation of galantamine analogues for cognitive improvement in Alzheimer's disease.

Galantamine plays a crucial role in the management of brain disorders. In this study, a series of galantamine analogues were designed, synthesized and evaluated as potential therapeutic agents for Alzheimer's disease (AD). Compound C2, a dual inhibitor of cholinesterase, was obtained by introducing a benzylpyridine ring to the hydroxyl group of galantamine.

A Collection of Novel Antitumor Agents That Regulate Lipid Metabolism in the Tumor Microenvironment.

Lipid metabolism disorder is the cause of one of the most significant metabolic changes in tumors. In the process of tumor occurrence and development, tumor cells choose a continuous metabolic adaptation to accommodate the changing environment to the maximum extent possible. In a variety of tumors, the uptake, production, and storage of lipids are generally upregulated.

Discovery of Novel 4,5,6,7-Tetrahydro-7-pyrazolo[3,4-]pyridin-7-one Derivatives as Orally Efficacious ATX Allosteric Inhibitors for the Treatment of Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is a progressive, fatal lung disease lacking effective treatments. Autotaxin (ATX) plays a crucial role in exacerbating inflammation and fibrosis, making it a promising target for fibrosis therapies. Herein, starting from PAT-409 (Cudetaxestat), a series of novel ATX inhibitors bearing 1-indole-3-carboxamide, 4,5,6,7-tetrahydro-7-pyrazolo[3,4-]pyridin-7-one, or 4,5,6,7-tetrahydro-1-pyrazolo[4,3-]pyridine cores were designed based on the structure of ATX hydrophobic tunnel.

Structure-based design of covalent nanobody binders for a thermostable green fluorescence protein.

The use of green fluorescence protein (GFP) has advanced numerous areas of life sciences. An ultra-thermostable GFP (TGP), engineered from a coral GFP, offers potential advantages over traditional jellyfish-derived GFP because of its high stability. However, owing to its later discovery, TGP lacks the extensive toolsets available for GFP, such as heavy chain-only antibody binders known as nanobodies.

Recent Advances in enhancer of zeste homolog 2 Inhibitors: Structural insights and therapeutic applications.

Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in many malignancies and plays a critical role in cancer progression. Therefore, it is considered a promising target for therapeutic intervention. Although several EZH2 inhibitors have entered clinical trials, only one has received FDA approval.