Koh Sakano, Kairi Furui, Apakorn Kengkanna, Yuta Kikuchi, Masahito Ohue
{"title":"Chemical language models for natural product discovery.","authors":"Koh Sakano, Kairi Furui, Apakorn Kengkanna, Yuta Kikuchi, Masahito Ohue","doi":"10.1039/d6np00002a","DOIUrl":"10.1039/d6np00002a","url":null,"abstract":"<p><p>Covering: up to 2026Natural products are an important source of medicines, yet their discovery can be a slow and laborious process. The recent development of chemical language models (CLMs), which process string-based molecular representations, is reshaping the field of natural product science. This review provides an overview of the role of CLMs in natural product drug discovery, tracing their evolution from early neural networks to modern large-scale Transformers. We describe how these models accelerate discovery timelines by predicting bioactivity, biosynthetic pathways, and spectral data. Furthermore, we cover their use in proposing novel, natural-product-like scaffolds that expand the computationally explored chemical space. The review also addresses persistent challenges, including the limited availability of natural product data and the need for model interpretability. Finally, we discuss future directions, outlining the current status and prospects for CLM-enabled natural product science.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christopher C Thornburg, Rohitesh Kumar, Dongdong Wang, Barry R O'Keefe, Tanja Grkovic
{"title":"Structural determination of natural products at speeds and scale of high-throughput screening.","authors":"Christopher C Thornburg, Rohitesh Kumar, Dongdong Wang, Barry R O'Keefe, Tanja Grkovic","doi":"10.1039/d6np00016a","DOIUrl":"10.1039/d6np00016a","url":null,"abstract":"<p><p>Covering 2000 up to 2025.This review assesses analytical techniques available for routine structural elucidation of small molecules as part of high-throughput screening campaigns of natural product libraries. The emphasis is on the speed and scale of task management and highlights advances in technologies and library tools that enable the structural elucidation of complex molecules on small-scale and rapid timelines. We present the state of the art in the natural product field and provide a critical assessment of available techniques and tools, with a focus on the ability to analyze large numbers of samples in short timelines that can meet the speed and scale of high-throughput screening.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13159620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Renia Fotiadou, Florian Heinz, Konstantin F G Weigmann, Mark Doerr, Uwe T Bornscheuer, Ioannis V Pavlidis
{"title":"High-throughput assays for SAM-dependent methyltransferases: advances, challenges, and future perspectives.","authors":"Renia Fotiadou, Florian Heinz, Konstantin F G Weigmann, Mark Doerr, Uwe T Bornscheuer, Ioannis V Pavlidis","doi":"10.1039/d6np00006a","DOIUrl":"https://doi.org/10.1039/d6np00006a","url":null,"abstract":"<p><p>Covering: up to January 2026Methyltransferases (EC 2.1.1.-) represent one of the most functionally diverse enzyme families in biology. Found across all domains of life-including bacteria, archaea, eukaryotes, and viruses-these enzymes catalyze a wide range of methylation reactions, commonly on <i>O</i>-, <i>N</i>-, and <i>C</i>-atoms, in a chemo- and regioselective manner. The wide set of substrates methylated is why a universal assay for the methyltransferase's activity screening has not yet been established. Despite this diversity, most methyltransferases utilize a common methyl donor, the <i>S</i>-adenosyl-L-methionine (SAM). This shared feature has enabled the development of several assay strategies based on the detection of <i>S</i>-adenosyl-L-homocysteine, the by-product of SAM-dependent methylation, or its degradation products. Colorimetric and fluorometric assays have been widely employed to monitor methyltransferase activity, each with distinct advantages and limitations, depending on the substrate/product detection of the methylation reaction, but also whether they require purified enzymes or work in crude (<i>E. coli</i>) cell lysates. However, the methylation of substrates with more than one nucleophilic atom requires sophisticated analytical tools for accurate monitoring of the regiospecificity of methyltransferases. This complexity often limits the broader exploitation of methyltransferases, particularly in enzyme engineering efforts, where large datasets are generated and must be efficiently analyzed. This review critically examines the high-throughput screening assays developed to date for methyltransferase activity.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147830904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hot off the Press","authors":"Robert A. Hill and Andrew Sutherland","doi":"10.1039/D6NP90014C","DOIUrl":"10.1039/D6NP90014C","url":null,"abstract":"<p >A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as spectaterpenoid A from <em>Aspergillus spectabilis</em>.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" 4","pages":" 585-589"},"PeriodicalIF":10.6,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147696901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Glucose 6-phosphate: the diversity of <i>C</i>-methylation in sugar moieties within natural product biosynthesis.","authors":"Ziruo Zou, Michael Müller","doi":"10.1039/d5np00071h","DOIUrl":"https://doi.org/10.1039/d5np00071h","url":null,"abstract":"<p><p>Covering: Up to 2026Methylation is one of the most frequent and functionally significant modifications in natural product biosynthesis. This transformation generally involves the cosubstrate <i>S</i>-adenosyl-L-methionine (SAM) and occurs with high regio-, chemo-, and stereo-selectivity. <i>C</i>-Methylation serves as an effective strategy for the incorporation of C<sub>1</sub> building blocks and plays a key role in both carbon skeleton extension and structural core decoration. A notable example is SAM-dependent <i>C</i>-methylation of nucleotide-activated sugar moieties catalyzed by <i>C</i>-methyltransferase (<i>C</i>-MT) during the biosynthesis of glycosylated natural products. A prerequisite in these pathways is the activation of the sugar by the attachment of a nucleotide diphosphate (NDP) tail. Sugar <i>C</i>-MTs exhibit remarkable substrate specificity and often act in concert with additional transformations, such as oxidation, decarboxylation, or reduction, to diversify sugar structures. Canonical SAM-dependent sugar <i>C</i>-MTs are capable of introducing methyl groups at C3, C4, or C5 positions of the sugar ring by an S<sub>N</sub>2-like mechanism involving enolate intermediates. In contrast, C6 methylation has been attributed to radical SAM enzymes. These distinct strategies illustrate the enzymatic versatility and sophisticated control over sugar <i>C</i>-methylation in nature, contributing to the structural diversity of natural products.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Brief overview of recently reported misassigned natural products and their <i>in silico</i> revisions enabled by DU8ML, a machine learning-augmented DFT computational NMR method.","authors":"Srinivas Beduru, Andrei G Kutateladze","doi":"10.1039/d5np00088b","DOIUrl":"https://doi.org/10.1039/d5np00088b","url":null,"abstract":"<p><p>Covering: 2018 to 2025This <i>Highlight</i> article describes a personal selection of recent misassigned structures of natural products and their revision with the aid of DU8ML, a machine learning-augmented DFT computational method for fast and accurate calculations of solution NMR chemical shifts and spin-spin coupling constants.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sidharth Jayachandran, Adrian Enrique Gadar-Lopez, Ling Chen, Kasper Krunderup Jakobsen, Coco Xie, Therese Horch, Jay D. Keasling and Pablo Cruz-Morales
{"title":"Synthetic biology for heterologous expression and engineering of fungal polyketide synthases","authors":"Sidharth Jayachandran, Adrian Enrique Gadar-Lopez, Ling Chen, Kasper Krunderup Jakobsen, Coco Xie, Therese Horch, Jay D. Keasling and Pablo Cruz-Morales","doi":"10.1039/D5NP00020C","DOIUrl":"10.1039/D5NP00020C","url":null,"abstract":"<p>Covering: up to 2025</p><p>Polyketide synthases (PKSs) are essential enzymatic systems that produce a wide range of natural products. Their biosynthetic features offer significant opportunities to create a broad range of polyketides for pharmaceutical, agricultural, and biotechnology applications. In this highlight article, we provide a brief overview of key aspects of PKS biosynthesis, their classification in bacteria and fungi, and the evolutionary mechanisms driving their diversification. After outlining the fundamentals of PKSs, we discuss two key design principles for fungal PKS engineering: host selection and engineering strategies. For host selection, we revisit the state of the art in heterologous expression in yeast and filamentous fungi. We then explore strategies for modifying fungal PKS activity through starter unit selection, point mutations, and domain swaps. Finally, we offer perspectives on future directions for fungal PKS engineering, highlighting the importance of exploring new hosts and integrating advanced computational tools.</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" 3","pages":" 401-414"},"PeriodicalIF":10.6,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147324004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessandra S. Eustaquio, Eriko Takano and Tobias A. M. Gulder
{"title":"Editorial: Microbial host and metabolic engineering for natural product discovery and production","authors":"Alessandra S. Eustaquio, Eriko Takano and Tobias A. M. Gulder","doi":"10.1039/D6NP90006B","DOIUrl":"10.1039/D6NP90006B","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":" 2","pages":" 279-280"},"PeriodicalIF":10.6,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Engineering microbiomes for natural product discovery and production","authors":"Francesco Del Carratore , Rainer Breitling","doi":"10.1039/d5np00038f","DOIUrl":"10.1039/d5np00038f","url":null,"abstract":"<div><div>Covering: 2021 to 2025</div></div><div><div>Microbial communities represent a vast and largely untapped source of natural products with potential applications in various fields, including medicine, agriculture, and the biomanufacturing industry. Secondary metabolites play a crucial role in mediating interspecies interactions within these communities, influencing their structure and function. Recent advances in microbial genetic engineering and multi-omics technologies have enabled the harnessing of these interactions for enhanced natural product discovery and production. These techniques, coupled with systems biology and mathematical modelling, allow for the rational design and manipulation of microbial consortia to elicit the expression of cryptic biosynthetic gene clusters and to optimize the production of desired compounds. Additionally, direct mining of microbiomes using metagenomics, metatranscriptomics, and metabolomics has revealed a wealth of novel biosynthetic gene clusters and secondary metabolites with potential therapeutic and industrial value. Despite the challenges associated with cultivating and characterizing diverse microbial species, ongoing advancements in computational tools and data analysis are rapidly expanding our ability to explore and exploit the seemingly inexhaustible reservoir of natural products hidden within microbial communities.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 2","pages":"Pages 301-312"},"PeriodicalIF":10.6,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benjamin Philmus , Nicole E. Avalon , Yousong Ding , Drew T. Doering , Alessandra S. Eustáquio , William H. Gerwick , Hendrik Luesch , Jimmy Orjala , Shaz Sutherland , Arnaud Taton , Daniel Udwary
{"title":"Green genes from blue greens: challenges and solutions to unlocking the potential of cyanobacteria in drug discovery","authors":"Benjamin Philmus , Nicole E. Avalon , Yousong Ding , Drew T. Doering , Alessandra S. Eustáquio , William H. Gerwick , Hendrik Luesch , Jimmy Orjala , Shaz Sutherland , Arnaud Taton , Daniel Udwary","doi":"10.1039/d5np00016e","DOIUrl":"10.1039/d5np00016e","url":null,"abstract":"<div><div>Cyanobacteria are prolific producers of biologically active compounds that are important in influencing ecology, behavior of interacting organisms, and as leads in drug discovery efforts. Here we discuss the challenges faced by all natural product researchers, especially those that focus on cyanobacteria, and then describe progress that has been made in these areas. We also propose some solutions, paths forward, and thoughts for consideration on these challenges.</div></div>","PeriodicalId":94,"journal":{"name":"Natural Product Reports","volume":"43 2","pages":"Pages 286-300"},"PeriodicalIF":10.6,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}