Identification of an Unexplored Dynamic Allosteric Site on the Activation Pathway of the Vasopressin V2 Receptor.

Allostery governs the functional dynamics of proteins by regulating their conformational transitions. A major challenge lies in identifying dynamic allosteric sites, which are often not discernible from static structural data. Here, we developed an integrative computational framework combining molecular dynamics (MD) simulations, Markov state modeling (MSM), and mutual information (MI) analysis to investigate the vasopressin V2 receptor (V2R).

ReO-Catalyzed Intermolecular Dehydrative Friedel-Crafts Reaction of Aliphatic Alcohols.

In this paper, we describe an operationally facile and generally applicable intermolecular dehydrative Friedel-Crafts reaction for aliphatic alcohols via ReO catalysis in hexafluoroisopropanol (HFIP). This method obviates the need for highly corrosive Brønsted acids or strong Lewis acids; therefore, it is convenient to perform and offers improved functional group tolerance. DFT calculations suggested that the hydrogen-bonding interactions between HFIP and the perrhenate moiety significantly lowered the energetic barrier for catalytic C-O bond cleavage in aliphatic alcohols.

A Case Study Using DFT Calculation Aided Experimental Teaching of Organic Chemistry: Take the Ethyl Acetate Synthesis Experiment as an Example.

Organic chemistry is an important basic course in the field of natural science, and its experimental teaching is also an important part of this course. How can students acquire practical ability in experimental practice within the limited class hours? Our organic chemistry experimental teaching team has developed a teaching model using density functional theory (DFT) calculation-aided experimental teaching of organic chemistry. In this paper, taking the ethyl acetate synthesis experiment as an example, we provided a case study using DFT calculation-aided experimental teaching of organic chemistry.

Correction: TBAI-mediated electrochemical oxidative synthesis of quinazolin-4(3)-ones from 2-aminobenzamides and isothiocyanates.

Correction for 'TBAI-mediated electrochemical oxidative synthesis of quinazolin-4(3)-ones from 2-aminobenzamides and isothiocyanates' by Jingbin Huang , , 2025, , 4860-4865, https://doi.org/10.1039/d5ob00410a.

TBAI-mediated electrochemical oxidative synthesis of quinazolin-4(3)-ones from 2-aminobenzamides and isothiocyanates.

A practical protocol has been established to access 2-aminoquinazolin-4(3)-one derivatives through the electrochemical desulfurative cyclization of 2-aminobenzamides and isothiocyanates. The protocol allows for the formation of C-N bonds under mild conditions without metal catalysts or external oxidants. The practicability of this strategy is demonstrated by its broad substrate scope, good functional group compatibility, and scale-up synthesis.

Electrochemical Synthesis of 2-Amino-1,3-benzoxazines via TBAI-mediated Desulfurative Cyclization of Isothiocyanates and 2-Aminobenzyl Alcohols.

An efficient one-step protocol has been developed to access a variety of 2-amino-1,3-benzoxazine derivatives via tetrabutylammonium iodide-mediated electrochemical desulfurative cyclization of isothiocyanates and 2-aminobenzyl alcohols. The reaction proceeds through a cycle involving iodine generation, desulfurative cyclization, and iodide regeneration, efficiently forming intermolecular C-O and C-N bonds and affording 2-amino-1,3-benzoxazines in moderate to excellent yields. The practical utility of this strategy is evidenced by its broad substrate scope, good functional group compatibility, scalability to gram-scale synthesis, and metal- and oxidant-free conditions.

Gentiopicroside Attenuates Lithium/Pilocarpine-Induced Epilepsy Seizures by Down-Regulating NR2B/CaMKII/CREB and TLR4/NF-κB Signaling Pathways in the Hippocampus of Mice.

Epilepsy is a prevalent and disabling neurological condition characterized by recurrent seizures. Approximately 50% of adults with active epilepsy have at least one comorbidity and they are at a greater risk of premature death than the general population. Gentiopicroside (Gent) is a primary component of Pall.

Metabotropic Glutamate Receptor 5: A Potential Target for Neuropathic Pain Treatment.

Neuropathic pain, a multifaceted and incapacitating disorder, impacts a significant number of individuals globally. Despite thorough investigation, the development of efficacious remedies for neuropathic pain continues to be a formidable task. Recent research has revealed the potential of metabotropic glutamate receptor 5 (mGlu5) as a target for managing neuropathic pain.

Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5.

Two-thirds of signaling hormones and one-third of approved drugs exert their effects by binding and modulating the G protein-coupled receptors (GPCRs) activation. While the activation mechanism for monomeric GPCRs has been well-established, little is known about GPCRs in dimeric form. Here, by combining transition pathway generation, extensive atomistic simulation-based Markov state models, and experimental signaling assays, we reveal an asymmetric, stepwise millisecond allosteric activation mechanism for the metabotropic glutamate receptor subtype 5 receptor (mGlu5), an obligate dimeric class C GPCR.

Traditional Chinese medicines derived natural inhibitors of ferroptosis on ischemic stroke.

Ischemic stroke (IS) is a globally prevalent cerebrovascular disorder resulting from cerebral vessel occlusion, leading to significant morbidity and mortality. The intricate pathological mechanisms underlying IS complicate the development of effective therapeutic interventions. Ferroptosis, a form of programmed cell death (PCD) characterized by iron overload and accumulation of lipid peroxidation products, has been increasingly recognized as a key contributor to IS pathology.

Sepiolite-Supported Manganese Oxide as an Efficient Catalyst for Formaldehyde Oxidation: Performance and Mechanism.

The current study involved the preparation of a number of MnO/Sep catalysts using the impregnation (MnO/Sep-I), hydrothermal (MnO/Sep-H), and precipitation (MnO/Sep-P) methods. The MnO/Sep catalysts that were produced were examined for their ability to catalytically oxidize formaldehyde (HCHO). Through the use of several technologies, including N adsorption-desorption, XRD, FTIR, TEM, H-TPR, O-TPD, CO-TPD, and XPS, the function of MnO in HCHO elimination was examined.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells.

G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.

G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class of drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects or allosteric effects, and biased signaling or balanced signaling, characterize the complexity of GPCR dynamic features. In this study, we first review the structural advancements, activation mechanisms, and functional diversity of GPCRs.

Mechanism of NLRP3 Inflammasome in Epilepsy and Related Therapeutic Agents.

Epilepsy is one of the most widespread and complex diseases in the central nervous system (CNS), affecting approximately 65 million people globally, an important factor resulting in neurological disability-adjusted life year (DALY) and progressive cognitive dysfunction. Medication is the most essential treatment. The currently used drugs have shown drug resistance in some patients and only control symptoms; the development of novel and more efficacious pharmacotherapy is imminent.

Copper-catalyzed oxidative cyclization of 2-(1-pyrrol-1-yl)aniline and alkylsilyl peroxides: a route to pyrrolo[1,2-]quinoxalines.

An efficient method was developed for the one-pot construction of pyrrolo[1,2-]quinoxalines a Cu(II)-catalyzed domino reaction between 2-(1-pyrrol-1-yl)anilines and alkylsilyl peroxides. This reaction proceeds through C-C bond cleavage and new C-C and C-N bond formation. A mechanistic study suggests that alkyl radical species participate in the cascade reaction.

Antidepressant effect of the novel histone deacetylase-5 inhibitor T2943 in a chronic restraint stress mouse model.

Depression is a prevalent and debilitating psychiatric illness. However, the antidepressant drugs currently prescribed are only effective in a limited group of patients. Histone modifications mediated by histone acetylation are considered to play an important role in the pathogenesis and treatment of depression.

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Neuropathic pain is a debilitating pathological condition that presents significant therapeutic challenges in clinical practice. Unfortunately, current pharmacological treatments for neuropathic pain lack clinical efficacy and often lead to harmful adverse reactions. As G protein-coupled receptors (GPCRs) are widely distributed throughout the body, including the pain transmission pathway and descending inhibition pathway, the development of novel neuropathic pain treatments based on GPCRs allosteric modulation theory is gaining momentum.

Asperosaponin VI protects against spermatogenic dysfunction in mice by regulating testicular cell proliferation and sex hormone disruption.

Ethnopharmacological Relevance: Studies have found that the causes of male infertility are complex, and spermatogenic dysfunction accounts for 30%-65% of male infertility causes, which is the main cause of male infertility. Asperosaponin VI (ASVI) is a saponin extracted from the traditional Chinese herb Dipsacus asperoides C.Y.

Pharmacologically targeting intracellular allosteric sites of GPCRs for drug discovery.

G-protein-coupled receptors (GPCRs) are a family of cell surface proteins that can sense a variety of extracellular stimuli and mediate multiple signaling transduction pathways involved in human physiology. Recent advances in GPCR structural biology have revealed a relatively conserved intracellular allosteric site in multiple GPCRs, which can be utilized to modulate receptors from the inside. This novel intracellular site partially overlaps with the G-protein and β-arrestin coupling sites, providing a novel avenue for biological intervention.