Communications Chemistry最新文献_第8页

Cryo-EM structure of amyloid fibrils formed by full-length human αA-crystallin with pathogenic mutation R116C. 致病性突变R116C的全长人α a -晶体蛋白形成的淀粉样蛋白原纤维的低温电镜结构。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-06 DOI: 10.1038/s42004-025-01637-5

Meinai Song, Jianting Han, Qin Cao

{"title":"Cryo-EM structure of amyloid fibrils formed by full-length human αA-crystallin with pathogenic mutation R116C.","authors":"Meinai Song, Jianting Han, Qin Cao","doi":"10.1038/s42004-025-01637-5","DOIUrl":"10.1038/s42004-025-01637-5","url":null,"abstract":"The aggregation of crystallin proteins in human lens is the primary cause of cataracts, a disease that leads to blindness of tens of millions of people worldwide. Understanding the molecular architectures of these aggregated crystallin proteins can facilitate the development of therapeutic drugs to treat cataract without surgery. In this study, we prepared two types of crystallin fibrils, thick and thin, using recombinant human αA-crystallin harboring the disease-associated R116C mutation under neutral and acidic conditions, respectively. The structure of the thin fibrils was determined via cryo-EM at a resolution of 3.7 Å, whereas the thick fibrils appeared unsuitable for cryo-EM structure determination. Structure analysis suggests that the thin fibrils adopt a three-layered structure stabilized by extensive steric zipper interactions. The observation of aspartate and glutamate ladders stacking along the fibril axis is consistent with the preference for an acidic environment of the thin fibrils. Disease mutations on Arg49 and Arg54 appear to facilitate the fibril structure, suggesting the potential disease relevance of these fibrils. Taken together, our study provides the first near-atomic resolution structure of aggregated crystallin and may facilitate the future studies on the mechanism and therapeutic of cataracts.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"233"},"PeriodicalIF":6.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chemical autoligation with phosphorothioate- and sulfonamide-terminated DNA via intramolecular cross-activation. 通过分子内交叉活化与硫代酸和磺胺末端DNA的化学自交联。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-06 DOI: 10.1038/s42004-025-01631-x

Hayato Yokoe, Kengo Kokubo, Kazuki Yamaoka, Ryota Oikawa, Fumiaki Tomoike, Naoko Abe, Yasuaki Kimura, Hiroshi Abe

引用次数: 0

Synthesis of Acinetobacter baumannii Lipid A(s) and derivatives and their structure-immunostimulatory activity relationships. 鲍曼不动杆菌脂质A(s)及其衍生物的合成及其结构-免疫刺激活性关系。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-06 DOI: 10.1038/s42004-025-01628-6

Xin-Ru Li, Janet Jia-Yin Tan, Chiao-Wen Chen, Jhen-Yan Huang, Hsien-Ya Lin, Boon Hee Goh, Keng-Chang Tsai, Chun-Hung Lin, Kwok-Kong Tony Mong

{"title":"Synthesis of Acinetobacter baumannii Lipid A(s) and derivatives and their structure-immunostimulatory activity relationships.","authors":"Xin-Ru Li, Janet Jia-Yin Tan, Chiao-Wen Chen, Jhen-Yan Huang, Hsien-Ya Lin, Boon Hee Goh, Keng-Chang Tsai, Chun-Hung Lin, Kwok-Kong Tony Mong","doi":"10.1038/s42004-025-01628-6","DOIUrl":"10.1038/s42004-025-01628-6","url":null,"abstract":"Acinetobacter baumannii emerges as one of the most worrisome pathogens causing a majority of hospital-acquired infections worldwide. However, the knowledge of its virulence factors remains obscure, in particular the bacterial lipooligosaccharides (LOS). Lipid A of the bacterial LOS exists as an inseparable mixture of homologues, making it impossible to study the immunological activity of each component. We herein report the synthesis of A. baumannii lipid A(s) (1-4) and corresponding monophosphate derivatives (1', 3' and 4'). The synthetic scheme features a short and stereoselective preparation of β-hydroxy acids and a convergent assembly of lipid A species with diverse structures. Subsequent immunological studies indicate that A. baumannii lipid A (2) having a [4 + 2]-acylation pattern displays the highest stimulatory potency. Further computational studies suggest that 2 and E. coli lipid A (5) sharing the same acylation pattern adopt an inverted binding mode in the TLR4/MD-2 receptor complex.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"234"},"PeriodicalIF":6.2,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Leveraging tree-transformer VAE with fragment tokenization for high-performance large chemical model generation. 利用带有片段标记化的树转换器VAE来生成高性能的大型化学模型。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-05 DOI: 10.1038/s42004-025-01640-w

Tensei Inukai, Aoi Yamato, Manato Akiyama, Yasubumi Sakakibara

{"title":"Leveraging tree-transformer VAE with fragment tokenization for high-performance large chemical model generation.","authors":"Tensei Inukai, Aoi Yamato, Manato Akiyama, Yasubumi Sakakibara","doi":"10.1038/s42004-025-01640-w","DOIUrl":"10.1038/s42004-025-01640-w","url":null,"abstract":"Molecular generation models, especially chemical language model (CLM) utilizing SMILES, a string representation of compounds, face limitations in handling large and complex compounds while maintaining structural accuracy. To address these challenges, we propose the Fragment Tree-Transformer based VAE (FRATTVAE), which treats molecules as tree structures with fragments as nodes. FRATTVAE incorporates several innovative techniques to enhance molecular generation. Molecules are decomposed into fragments and organized into tree structures, allowing for efficient handling of large and complex compounds. Tree positional encoding assigns unique positional information to each fragment, preserving hierarchical relationships. The Transformer's self-attention mechanism models complex dependencies among fragments. This architecture allows FRATTVAE to surpass existing methods, making it a robust solution that is scalable to unprecedented dataset sizes and molecular complexities. Distribution learning across various benchmark datasets, from small molecules to natural compounds, showed that FRATTVAE consistently achieved high accuracy in all metrics while balancing reconstruction accuracy and generation quality. In molecular optimization tasks, FRATTVAE generated high-quality, stable molecules with desired properties, avoiding structural alerts. These results highlight FRATTVAE as a robust and versatile solution for molecular generation and optimization, making it well-suited for a variety of applications in cheminformatics and drug discovery.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"228"},"PeriodicalIF":6.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations. 通过分子模拟研究HCV药物类似物的三维构象和晶体相互作用对药物开发的挑战。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-05 DOI: 10.1038/s42004-025-01618-8

Richard S Hong, Alessandra Mattei, Mark E Tuckerman, Ahmad Y Sheikh

{"title":"3D conformation and crystal interaction insights into drug development challenges for HCV drug analogues via molecular simulations.","authors":"Richard S Hong, Alessandra Mattei, Mark E Tuckerman, Ahmad Y Sheikh","doi":"10.1038/s42004-025-01618-8","DOIUrl":"10.1038/s42004-025-01618-8","url":null,"abstract":"ABT-333 and ABT-072 are two potent non-nucleoside NS5B polymerase inhibitors designed for the treatment of the hepatitis C virus (HCV). These structural analogs differ only by a minor substituent change, which disrupts the planarity of the naphthyl group on the ABT-333 compound through the addition of a more flexible trans-olefin substituent. However, this minor change leads to significant differences in their conformational preferences and intermolecular interactions, resulting in a ripple effect with drug development implications, ranging from crystal polymorphism and low aqueous solubility to formulation development challenges. In this article, we demonstrate how a suite of molecular simulation approaches, including crystal structure prediction augmented with a new hydrate CSP algorithm, free-energy perturbation, molecular dynamics (MD) based solubility predictions, and topological assessment to evaluate surface re-crystallization tendencies, provide key atomistic-level insights into the differentiated performance of the two analogs. Through this study, we establish the importance of end-to-end physics-based modeling, which involves explicit considerations of 3-D structure and crystal packing interactions. This approach provides structural and energetic insights into the physicochemical properties and drug development challenges faced when designing best-in-class drug molecules.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"229"},"PeriodicalIF":6.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12325785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Solution structure of Titan-relevant aqueous ammonia by neutron diffraction. 用中子衍射分析钛相关氨水溶液的结构。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-02 DOI: 10.1038/s42004-025-01599-8

Mazin Nasralla, Harrison Laurent, Oliver L G Alderman, Lorna Dougan

引用次数: 0

Pathway regulation mechanism by cotranslational protein folding. 共翻译蛋白折叠的通路调控机制。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-01 DOI: 10.1038/s42004-025-01636-6

Peng Tao, Yi Xiao

{"title":"Pathway regulation mechanism by cotranslational protein folding.","authors":"Peng Tao, Yi Xiao","doi":"10.1038/s42004-025-01636-6","DOIUrl":"10.1038/s42004-025-01636-6","url":null,"abstract":"Existing experimental results indicate potential disparities between cotranslational protein folding in vivo and free folding in vitro, yet the microscopic mechanisms responsible for these differences remain elusive. In this study, we devised a general protein cotranslational folding (GPCTF) simulations framework by modeling the ribosomal exit tunnel and translation process. Utilizing the GPCTF framework, we conducted extensive molecular dynamics simulations on three proteins of varying topologies, generating over 8 milliseconds of total trajectories. When compared to free folding, cotranslational folding enables the nascent peptide to adopt a more helix-rich structure with less nonnative interactions upon expulsion from the ribosomal exit tunnel. Notably, subsequent folding of this structure adheres to the same pathway as free folding, but with different ratios of folding pathways, modulated by the translation speed. This investigation illuminates the pathway regulation mechanism inherent to cotranslational folding and successfully reconciles discrepancies in pre-existing experimental results, offering significant insights into the protein folding process in vivo.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"226"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A bottom-up approach to find lead compounds in expansive chemical spaces. 一种在广阔的化学空间中寻找铅化合物的自下而上的方法。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-01 DOI: 10.1038/s42004-025-01610-2

Álvaro Serrano-Morrás, Andrea Bertran-Mostazo, Marina Miñarro-Lleonar, Arnau Comajuncosa-Creus, Adrià Cabello, Carme Labranya, Carmen Escudero, Tian V Tian, Inna Khutorianska, Dmytro S Radchenko, Yurii S Moroz, Lucas Defelipe, David Ruiz-Carrillo, Maria Garcia-Alai, Robert Schmidt, Matthias Rarey, Patrick Aloy, Carles Galdeano, Jordi Juárez-Jiménez, Xavier Barril

{"title":"A bottom-up approach to find lead compounds in expansive chemical spaces.","authors":"Álvaro Serrano-Morrás, Andrea Bertran-Mostazo, Marina Miñarro-Lleonar, Arnau Comajuncosa-Creus, Adrià Cabello, Carme Labranya, Carmen Escudero, Tian V Tian, Inna Khutorianska, Dmytro S Radchenko, Yurii S Moroz, Lucas Defelipe, David Ruiz-Carrillo, Maria Garcia-Alai, Robert Schmidt, Matthias Rarey, Patrick Aloy, Carles Galdeano, Jordi Juárez-Jiménez, Xavier Barril","doi":"10.1038/s42004-025-01610-2","DOIUrl":"10.1038/s42004-025-01610-2","url":null,"abstract":"Drug discovery starts with the identification of a \"hit\" compound that, following a long and expensive optimization process, evolves into a drug candidate. Bigger screening collections increase the odds of finding more and better hits. For this reason, large pharmaceutical companies have invested heavily in high-throughput screening (HTS) collections that can contain several million compounds. However, this figure pales in comparison with the emergent on-demand chemical collections, which have recently reached the trillion scale. These chemical collections are potentially transformative for drug discovery, as they could deliver many diverse and high-quality hits, even reaching lead-like starting points. But first, it will be necessary to develop computational tools capable of efficiently navigating such massive virtual collections. To address this challenge, we have conceived an innovative strategy that explores the chemical universe from the bottom up, performing a systematic search on the fragment space (exploration phase), to then mine the most promising areas of on-demand collections (exploitation phase). Using a hierarchy of increasingly sophisticated computational methods to remove false positives, we maximize the success probability and minimize the overall computational cost. A basic implementation of the concept has enabled us to validate the strategy prospectively, allowing the identification of new BRD4 (BD1) binders with potencies comparable to stablished drug candidates.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"225"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reference library for suspect screening of environmental toxicants using ion mobility spectrometry-mass spectrometry. 使用离子迁移谱-质谱法筛选环境毒物的参考文库。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-01 DOI: 10.1038/s42004-025-01619-7

Devin Teri, Noor A Aly, James N Dodds, Jian Zhang, Paul A Thiessen, Evan E Bolton, Kara M Joseph, Antony J Williams, Emma L Schymanski, Ivan Rusyn, Erin S Baker

{"title":"Reference library for suspect screening of environmental toxicants using ion mobility spectrometry-mass spectrometry.","authors":"Devin Teri, Noor A Aly, James N Dodds, Jian Zhang, Paul A Thiessen, Evan E Bolton, Kara M Joseph, Antony J Williams, Emma L Schymanski, Ivan Rusyn, Erin S Baker","doi":"10.1038/s42004-025-01619-7","DOIUrl":"10.1038/s42004-025-01619-7","url":null,"abstract":"Due to the potential health risks related to chemical exposure, rapidly assessing xenobiotic molecules in the environment and those already in the body is imperative. Targeted analytical methods coupling either gas or liquid chromatography with mass spectrometry (GC-MS or LC-MS) are commonly utilized in current exposure assessments. While these methods are accepted as the gold standard for exposure analyses, they often require multiple sample preparation steps and analysis times > 30 min. These limitations have resulted in an evolving interest in using ion mobility spectrometry and MS (IMS-MS), either with or without chromatography, to improve throughput and annotation confidence. To increase IMS-MS information availability for exposure studies, here we utilized drift tube IMS-MS to evaluate 4685 xenobiotic chemical standards from the Environmental Protection Agency Toxicity Forecaster (ToxCast) programme, including pesticides, industrial chemicals, pharmaceuticals, consumer products, and per- and polyfluoroalkyl substances. Collision cross section (CCS) and m/z values were detected for 2144 unique chemicals with high confidence and reproducibility (≤1% error intra-laboratory and ≤2% inter-laboratory), resulting in values for 4004 [M + H]+, [M+Na]+, [M-H]- and [M]•+ ion types. This multidimensional database therefore supports suspect screening for a wider range of environmental contaminants, faster exposure response times, and assessments of xenobiotic-disease connections.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"224"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Photo-CIDNP for quantification of micromolar analytes in urine. photocidnp用于尿液中微量摩尔分析物的定量。

IF 6.2 2区化学

Communications Chemistry Pub Date : 2025-08-01 DOI: 10.1038/s42004-025-01626-8

Marta Stefańska, Thomas Müntener, Sebastian Hiller

{"title":"Photo-CIDNP for quantification of micromolar analytes in urine.","authors":"Marta Stefańska, Thomas Müntener, Sebastian Hiller","doi":"10.1038/s42004-025-01626-8","DOIUrl":"10.1038/s42004-025-01626-8","url":null,"abstract":"Towards target diagnostics of low-concentrated molecules in biofluids, NMR spectroscopy faces limitations due to low sensitivity, signal overlap, and high equipment costs. Hyperpolarization methods such as photo-chemically induced dynamic nuclear polarization (photo-CIDNP) can mitigate some of these challenges. In this study, we explore the potential of steady-state photo-CIDNP to quantify target molecules in urine samples. Matrix interference poses a significant challenge to quantitative measurements, and we thus establish two counteracting methods: spiking and biofluid dilution. Experiments conducted in both high (14.1 T) and low (1.9 T) magnetic fields demonstrate the effectiveness of photo-CIDNP-based quantification at micromolar levels for the analytes sumatriptan and paracetamol. We report limits of quantification (LOQs) in complex matrices down to 3.5 μM and average errors of less than 26% with the spiking method and less than 11% using biofluid dilution. This proof-of-concept study highlights the potential of NMR supported by photo-CIDNP as a target diagnostic tool for rapid drug quantification and clinical monitoring applications, especially with low-cost benchtop NMR devices.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":"8 1","pages":"223"},"PeriodicalIF":6.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0