Fragment-Based Drug Design: From Then until Now, and Toward the Future.

Fragment-based drug design (FBDD) has emerged as a powerful strategy in drug discovery, offering a complementary approach to traditional high-throughput screening (HTS)-based drug discovery. Over almost half a century, FBDD has undergone significant evolution, leading to the discovery of multiple approved drugs in the market. The integration of structural and computational tools into FBDD has significantly enhanced its efficiency, facilitating rational drug design.

Leveraging Structural and Computational Biology for Molecular Glue Discovery.

The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin-proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues.

Hyaluronan-decorated CuO-doxorubicin nanodot clusters for targetedly sensitizing cuproptosis in breast cancer via a three-pronged strategy.

Cuproptosis shows great prospects in cancer treatments. However, insufficient intracellular copper amount, low-level redox homeostasis, and hypoxic tumor microenvironment severely restrict cuproptosis efficacy. Herein, hydrazided hyaluronan-templated decorated CuO-doxorubicin (CuDT) nanodot clusters (NCs) are developed for efficient doxorubicin (DOX)-sensitized cuproptosis therapy in breast cancer via a three-pronged strategy.

Cigarette smoke components modulate the MR1-MAIT axis.

Tobacco smoking is prevalent across the world and causes numerous diseases. Cigarette smoke (CS) compromises immunity, yet little is known of the components of CS that impact T cell function. MR1 is a ubiquitous molecule that presents bacterial metabolites to MAIT cells, which are highly abundant in the lungs.

A cost-effective climate mitigation pathway for China with co-benefits for sustainability.

Climate mitigation policies have broad environmental and socioeconomic impacts and thus underpin progress towards the United Nations Sustainable Development Goals (SDGs). Through national-scale integrated modeling, we explore the spillover effects of China's long-term climate mitigation pathways (CMPs) on achieving all 17 SDGs, and then identify a cost-effective CMP for China with co-benefits for sustainability. Our analysis indicates that the 9 original CMPs and 180 bundled CMPs can both substantially boost the SDGs, resulting in an increase of 6.

Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics.

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads.

Current Status of Computational Approaches for Small Molecule Drug Discovery.

2024 has been an exciting year for computational sciences, with the Nobel Prize in Physics awarded for "artificial neural network" and the Nobel Prize in Chemistry presented for "protein structure prediction and design". Given the rapid advancements in Computer-Aided Drug Design (CADD) and Artificial Intelligence in Drug Discovery (AIDD), a document summarizing their current standing and future directions would be timely and relevant to the readership of . This piece of commentary aims to highlight recent developments, key challenges, and potential synergies between these fields, contributing to ongoing discussions in the literature and scientific blogs.

Hollow Calcium/Copper Bimetallic Amplifier for Cuproptosis/Paraptosis/Apoptosis Cancer Therapy via Cascade Reinforcement of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

The endoplasmic reticulum (ER) and mitochondria are essential organelles that play crucial roles in maintaining cellular homeostasis. The simultaneous induction of ER stress and mitochondrial dysfunction represents a promising yet challenging strategy for cancer treatment. Herein, a hollow calcium-copper bimetallic nanoplatform is developed as a cascade amplifier to reinforce ER stress and mitochondrial dysfunction for breast cancer treatment.

Comparative transcriptome profiling reveals the key genes and molecular mechanisms involved in rice under blast infection.

The aim of this study was to analyze the resistance genes and molecular mechanisms involved in rice blast infection. The contents of seven hormones and eight biochemical indicators in the leaves and spikes were at dynamic levels after inoculation with rice blast strains over time. The mRNA and protein expression of the six genes were consistent with the transcriptome analysis results.

Ultra-large scale virtual screening identifies a small molecule inhibitor of the Wnt transporter Wntless.

Wnts are lipid-modified glycoproteins that play key roles in both embryonic development and adult homeostasis. Wnt signaling is dysregulated in many cancers and preclinical data shows that targeting Wnt biosynthesis and secretion can be effective in Wnt-addicted cancers. An integral membrane protein known as Wntless (WLS/Evi) is essential for Wnt secretion.

High acidity organic waste degradation and the potential to bioremediation of heavy metals in soil by an acid-tolerant Serratia sp.

Highly acidic citrus pomace (CP) is a byproduct of Pericarpium Citri Reticulatae production and causes significant environmental damage. In this study, a newly isolated acid-tolerant strain of Serratia sp. JS-043 was used to treat CP and evaluate the effect of reduced acid citrus pomace (RACP) in passivating heavy metals.

Heterotrimeric collagen helix with high specificity of assembly results in a rapid rate of folding.

The most abundant natural collagens form heterotrimeric triple helices. Synthetic mimics of collagen heterotrimers have been found to fold slowly, even compared to the already slow rates of homotrimeric helices. These prolonged folding rates are not understood.

Self-assembled copper-based nanoparticles for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma.

As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu, 3,3'-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818.

SC-Unext: A Lightweight Image Segmentation Model with Cellular Mechanism for Breast Ultrasound Tumor Diagnosis.

Automatic breast ultrasound image segmentation plays an important role in medical image processing. However, current methods for breast ultrasound segmentation suffer from high computational complexity and large model parameters, particularly when dealing with complex images. In this paper, we take the Unext network as a basis and utilize its encoder-decoder features.

Molecular mechanisms of selenite reduction by Lactiplantibacillus plantarum BSe: An integrated genomic and transcriptomic analysis.

The reduction of selenite [Se(Ⅳ)] by microorganisms is a green and efficient detoxification strategy. We found that Se(Ⅳ) inhibited exopolysaccharide and protein secretion by Lactiplantibacillus plantarum BSe and compromised cell integrity. In this study, L.

Hyaluronan-decorated copper-doxorubicin-anlotinib nanoconjugate for targeted synergistic chemo/chemodynamic/antiangiogenic tritherapy against hepatocellular carcinoma.

Copper-based nanomaterials show considerable potential in the chemodynamic therapy of cancers. However, their clinical application is restricted by low catalytic activity in tumor microenvironment and copper-induced tumor angiogenesis. Herein, a novel copper-doxorubicin-anlotinib (CDA) nanoconjugate was constructed by the combination of copper-hydrazide coordination, hydrazone linkage and Schiff base bond.

Identification of small-molecule binding sites of a ubiquitin-conjugating enzyme-UBE2T through fragment-based screening.

UBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin-conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug-like small molecules. Here, we performed fragment screening using F-nuclear magnetic resonance (NMR) and validated the hits with H- N-heteronuclear single quantum coherence (HSQC) experiment and X-ray crystallographic studies.

Identification and characterization of inhibitors covalently modifying catalytic cysteine of UBE2T and blocking ubiquitin transfer.

UBE2T is an E2 ubiquitin ligase critical for ubiquitination of substrate and plays important roles in many diseases. Despite the important function, UBE2T is considered as an undruggable target due to lack of a pocket for binding to small molecules with satisfied properties for clinical applications. To develop potent and specific UBE2T inhibitors, we adopted a high-throughput screening assay and two compounds-ETC-6152 and ETC-9004 containing a sulfone tetrazole scaffold were identified.

Estimation of heart rate and respiratory rate by monitoring cardiopulmonary signals with flexible sensor.

Monitoring of cardiopulmonary signals plays an important role in many clinical applications. A portable magnetic induction cardiopulmonary signal monitoring system with the flexible sensor of double micro-coils is presented in this paper. The detection of cardiopulmonary signals is realized with double micro-coils.

Efficacy and potential therapeutic mechanism of Weiwei decoction on Spasmolytic polypeptide-expressing metaplasia in Helicobacter pylori-infected and Atp4a-knockout mice.

Ethnopharmacological Relevance: Spasmolytic polypeptide-expressing metaplasia (SPEM) is characterized by mucus cell morphologies at the base of gastric glands, which is considered advanced SPEM when accompanied with an increase in transcripts associated with intestinal-type gastric cancer. Weiwei decoction (WWD) was modified from "Si-Jun-Zi Tang," which has been used for thousands of years in China against gastric atrophy and metaplasia.

Aim Of The Study: To investigate the effects and potential mechanisms of WWD against advanced SPEM.

Hydrazide/Metal/Indocyanine Green Coordinated Nanoplatform for Potentiating Reciprocal Ferroptosis and Immunity against Melanoma.

Ferroptosis holds great potential in cancer treatment, but its efficacy is severely limited by a low Fenton reaction efficacy. Meanwhile, the interactive relationship between Ferroptosis and the PD-1 blockade is still vague. Herein, a hydrazide/Cu/Fe/indocyanine green coordinated nanoplatform (TCFI) is constructed by a hydrazide-metal-sulfonate coordination process.

Hepatocyte DDX3X protects against drug-induced acute liver injury via controlling stress granule formation and oxidative stress.

Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF). Continuous and prolonged hepatic cellular oxidative stress and liver inflammatory stimuli are key signatures of DILI. DEAD-box helicase 3, X-linked (DDX3X) is a central regulator in pro-survival stress granule (SG) assembly in response to stress signals.

Widely Targeted HPLC-MS/MS Metabolomics Analysis Reveals Natural Metabolic Insights in Insects.

Insect metabolites play vital roles in regulating the physiology, behavior, and numerous adaptations of insects, which has contributed to them becoming the largest class of Animalia. However, systematic metabolomics within the insects is still unclear. The present study performed a widely targeted metabolomics analysis based on the HPLC-MS/MS technology to construct a novel integrated metabolic database presenting comprehensive multimetabolite profiles from nine insect species across three metamorphosis types.

Tumor Microenvironment Responsive Hollow Nanoplatform for Triple Amplification of Oxidative Stress to Enhance Cuproptosis-Based Synergistic Cancer Therapy.

Cuproptosis is a recently discovered form of programmed cell death and shows great potential in cancer treatment. Herein, a copper-dithiocarbamate chelate-doped and artemisinin-loaded hollow nanoplatform (HNP) is developed via a chelation competition-induced hollowing strategy for cuproptosis-based combination therapy. The HNP exhibits tumor microenvironment-triggered catalytic activity, wherein liberated Cu catalyzes artemisinin and endogenous H O to produce C-centered radicals and hydroxyl radicals, respectively.