Chemical libraries articles within Nature Communications

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  • Article
    | Open Access

    Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.

    • Darryl M. Wilson
    • , Daniel J. Driedger
    •  & Robert A. Britton

  • Article
    | Open Access

    Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.

    • Arun Chandramohan
    • , Hubert Josien
    •  & Anthony W. Partridge

  • Article
    | Open Access

    Targeted protein degradation (TPD) is an emerging therapeutic that can lead to proteasomal degradation of target proteins. Here, the authors combine nano-scale, automated synthesis and cell-based, direct-to-biology screening, allowing them to discover and profile Molecular Glues (MGs) degrading substrates via the Cereblon E3 ubiquitin ligase.

    • Zefeng Wang
    • , Shabnam Shaabani
    •  & Alexander Dömling

  • Article
    | Open Access

    Minor changes to complex structures can exert major influences on synthesis strategy and functional properties but synthetic difficulties can obstruct the exploration of natural product function. Here the authors explore two parallel series of picrotoxinin analogs and identify leads with selectivity between mammalian and insect ion channels.

    • Guanghu Tong
    • , Samantha Griffin
    •  & Ryan A. Shenvi

  • Article
    | Open Access

    Most DNA-encoded library (DEL) syntheses are limited by the presence of sensitive DNA-based constructs. Here, the authors develop DOSEDO, a diverse 3.7 million compound DEL, generated through diversity-oriented synthesis that provides enhanced scaffold and exit vector diversity and gives validated binding hits for multiple protein targets.

    • Liam Hudson
    • , Jeremy W. Mason
    •  & Karin Briner

  • Article
    | Open Access

    Treatments to prevent thrombosis are suboptimal. Here, the authors identify a lead an antithrombotic drug targeting polyphosphate based on switchable protonation states for the anion-binding groups, demonstrating antithrombotic activity in multiple mouse models, not causing bleeding, and well tolerated.

    • Chanel C. La
    • , Stephanie A. Smith
    •  & Jayachandran N. Kizhakkedathu

  • Article
    | Open Access

    Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.

    • Jayme L. Dahlin
    • , Bruce K. Hua
    •  & Bridget K. Wagner

  • Article
    | Open Access

    Catalysed oxidative C-C bond formation reactions are important in the synthesis of natural products, but poorly tolerated by polyphenolic flavones. Here the authors report the reactivity of molecular oxygen in alkaline water without added catalyst for the synthesis of a collection of flavone dimers and trimers.

    • Xin Yang
    • , Sophie Hui Min Lim
    •  & Dejian Huang

  • Article
    | Open Access

    In vitro library screening is a powerful approach to identify functional biopolymers, but only covers a fraction of possible sequences. Here, the authors use experimental in vitro selection results to train a conditional variational autoencoder machine learning model that generates biopolymers with no apparent sequence similarity to experimentally derived examples, but that nevertheless bind the target molecule with similar potent binding affinity.

    • Jonathan C. Chen
    • , Jonathan P. Chen
    •  & David R. Liu

  • Article
    | Open Access

    Macrocycles have potential as therapeutics, but their libraries are currently not large enough for high-throughput screening. Here, the authors show a combinatorial approach to generate a library of almost 20’000 macrocycles by conjugating carboxylic-acid fragments to macrocyclic scaffolds, identifying nanomolar inhibitors against thrombin and binders of MDM2.

    • Sevan Habeshian
    • , Manuel Leonardo Merz
    •  & Christian Heinis

  • Article
    | Open Access

    Metabolic reprogramming contributes to cancer development and progression. Here, the authors show the utility of a metabolic drug library to uncover metabolic vulnerabilities and obtain functional insights into myeloid leukemia biology.

    • Tea Pemovska
    • , Johannes W. Bigenzahn
    •  & Giulio Superti-Furga

  • Article
    | Open Access

    2-Fluoroindoles are an important structural scaffold in many bioactive or therapeutic agents, but efficient constructions of 2-fluoroindole derivatives are very sparce. Here the authors report an efficient and general strategy for the construction of 2-fluoroindoles in which a wide variety of 2-fluoroindoles were accessed with high efficiency and chemoselectivity.

    • Jianke Su
    • , Xinyuan Hu
    •  & Qiuling Song

  • Article
    | Open Access

    Fragment-based drug discovery employs screening of small polar compounds typically exhibiting low affinity towards protein targets. Here, the authors combine the use of protein-based binding pharmacophores with the theory of protein hotspots to develop a design protocol for fragment libraries, called SpotXplorer, and validate their approach on common and emerging drug targets.

    • Dávid Bajusz
    • , Warren S. Wade
    •  & György M. Keserű

  • Article
    | Open Access

    Natural products inspire the development of pseudo-natural products through combinations of fragments of compound classes that are chemically and biologically distinct. Here, the authors report a library of 244 pseudo-natural products, evaluate them in the cell painting essays and identify the phenotypic role of individual fragments.

    • Michael Grigalunas
    • , Annina Burhop
    •  & Herbert Waldmann

  • Article
    | Open Access

    RaPID (Random non-standard Peptides Integrated Discovery) enables discovery of small macrocyclic peptides binding desired targets. Here, the authors propose lasso-grafting: the RaPID-derived peptides are implanted onto diverse proteins and maintain both the binding properties of the cyclic peptide and the host protein function.

    • Emiko Mihara
    • , Satoshi Watanabe
    •  & Junichi Takagi

  • Article
    | Open Access

    Vitamin B3 derivatives display a range of biological activities. Here, the authors report the synthesis of meta-aminoaryl nicotinates, derivatives of vitamin B3, and their late-stage conjugation with (hetero)arylamines, ultimately expanding the chemical space for biomedical research.

    • Begur Vasanthkumar Varun
    • , Kannan Vaithegi
    •  & Seung Bum Park

  • Article
    | Open Access

    On-chip synthesis and screening has been used to automate drug discovery but on-chip analysis still remains a major limitation. Here, the authors report on a dendrimer-based surface patterning method to create nanodroplet arrays on materials which allow for on-chip high-throughput analysis.

    • Maximilian Benz
    • , Arndt Asperger
    •  & Pavel A. Levkin

  • Article
    | Open Access

    The functionalization of a sulfur-sulfur motif is synthetically challenging but highly desired for the production of bioactive compounds. Here, the authors report a disulfurating reagent for sequential and modular assembly of polysulfides where the S-S motif is functionalized with different C-, N- and S-nucleophiles.

    • Jiahui Xue
    •  & Xuefeng Jiang

  • Article
    | Open Access

    Synthetic peptide libraries can access broad chemical space, but generally examine only ~ 106 compounds. Here, the authors show that in-solution affinity selection, interfaced with nLC-MS/MS sequencing, can identify binders from fully randomized synthetic libraries of 108 members.

    • Anthony J. Quartararo
    • , Zachary P. Gates
    •  & Bradley L. Pentelute

  • Article
    | Open Access

    Catalytic asymmetric hydrosilylation of internal alkenes has proven elusive due to more favourable double bond reduction or isomerization. Here, the authors show an enantioselective Si-C coupling by hydrosilylation of activated alkenes using a palladium/phosphoramidite catalyst affording axially chiral succinimides.

    • Xing-Wei Gu
    • , Yu-Li Sun
    •  & Li-Wen Xu

  • Article
    | Open Access

    One strategy to address multidrug resistance in cancer is the development of modular methods to access bioactive scaffolds. Here, the authors report a Rh(III)-catalyzed carboxylic acid-directed C(sp2)−H allylation and apply it to the modular synthesis of (Z)-allylic macrolides which enhance antitumoral drug activity.

    • Lu Chen
    • , Haitian Quan
    •  & Weibo Yang

  • Article
    | Open Access

    Bryostatin 1 is a unique therapeutic lead, however its scarce natural sources have hampered its use in treatment of human disease. Here, the authors use a scalable synthesis of bryostatin 1 to make close-in analogs which potently induce increased cell surface expression holding potential for immunotherapy.

    • Clayton Hardman
    • , Stephen Ho
    •  & Paul A. Wender

  • Article
    | Open Access

    Combining genome mining and heterologous expression in a genetically tractable host can lead to bioactive natural products discovery and production. Here, the authors employ this strategy for new decalin-containing diterpenoid pyrenes production by expressing native, extended, and shunt pathways in Aspergillus oryzae.

    • Kento Tsukada
    • , Shono Shinki
    •  & Teigo Asai

  • Article
    | Open Access

    Transition metal-catalysed C–H hydroxylation is one of the most notable synthetic advances to access alcohols and phenols. Here, the authors report a metal-free, mild C–H hydroxylation of (hetero)arenes via boron-mediated chelation.

    • Jiahang Lv
    • , Binlin Zhao
    •  & Zhuangzhi Shi

  • Article
    | Open Access

    Validating crosslinking-mass spectrometry workflows is hampered by the lack of a ground truth to assess the robustness of the crosslink identifications. Here, the authors present a synthetic library of crosslinked peptides, enabling unambiguous discrimination of correct and incorrect crosslink identifications.

    • Rebecca Beveridge
    • , Johannes Stadlmann
    •  & Karl Mechtler

  • Article
    | Open Access

    Derivatization of natural products is a powerful approach to generate new molecules for biological screenings. Here, the authors employ C-H oxidation and ring expansion methods for the preparation of a library of medium-sized ring skeleta, which occupy a unique chemical space based on chemoinformatic analysis.

    • Changgui Zhao
    • , Zhengqing Ye
    •  & Weiping Tang

  • Article
    | Open Access

    Dialkyl biaryl phosphines find wide application in catalysis as ligands. Here, the authors report a rhodium-catalysed hydroarylation of alkenes and alkynes with tertiary phosphines through P(III)-chelation assisted C-H activation affording a library of functionalized phosphines which hold potential in catalytic applications.

    • Dingyi Wang
    • , Ben Dong
    •  & Zhuangzhi Shi

  • Article
    | Open Access

    High-throughput cell-based screening of compound libraries is utilised in drug development; however, a lack of compatible methods limits direct synthesis and testing. Here, the authors present a diverse chip based synthesis system which can be combined with cell screening and demonstrate the application.

    • Maximilian Benz
    • , Mijanur R. Molla
    •  & Pavel A. Levkin

  • Article
    | Open Access

    Preparation of xanthene-containing compounds has been limited due to structural bias existing methods pose. Here, the authors developed a mild, diversity-oriented method for rhodamines synthesis, leading to the finding of compounds with antibacterial potency against a variety of bacterial species.

    • Xiao Luo
    • , Liujia Qian
    •  & Youjun Yang

  • Article
    | Open Access

    Designing molecular keys and combining advanced encryption standard cryptography with molecular steganography is a secure way for encoding messages. Here, the authors use the Ugi four-component reaction of perfluorinated acids to create a library of 500,000 molecular keys for encryption and decryption.

    • Andreas C. Boukis
    • , Kevin Reiter
    •  & Michael A. R. Meier

  • Article
    | Open Access

    Polycyclic meroterpenoids show a wide range of biological activities. Here, the authors report a modular approach to synthesize a number of natural and non-natural tetracyclic meroterpenoids, which display antibiotic activity against methicillin-resistant Staphylococcus aureus.

    • Raphael Wildermuth
    • , Klaus Speck
    •  & Thomas Magauer

  • Article
    | Open Access

    Heteroatom-rich organoboron compounds are promising modulators of enzyme activity. Here, the authors report a library of aminocyanoboronates as serine hydrolases inhibitors with the most potent compound showing in vivo and in vitro nanomolar activity and high selectivity towards human ABHD3 hydrolase.

    • Joanne Tan
    • , Armand B. Cognetta III
    •  & Andrei K. Yudin

  • Article
    | Open Access

    Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds forS. aureus, A. baumannii and M. tuberculosis.

    • Carl A. Machutta
    • , Christopher S. Kollmann
    •  & Ghotas Evindar

  • Article
    | Open Access

    Heterocycles are ubiquitous in bioactive compounds and routes to different substitution patterns are important to access the full substrate space. Here the authors report a route to 4,5,7,8-substituted antiviral fluorescent quinazolines, to allow cellular uptake visualization without external marker.

    • Felix E. Held
    • , Anton A. Guryev
    •  & Svetlana B. Tsogoeva

  • Article
    | Open Access

    Synthetic methods that efficiently construct structurally diverse molecular scaffolds are attractive routes to diversely bioactive molecules. Here the authors report a method whereby common starting materials are converted to structurally and functionally diverse products by changing the catalyst ligand.

    • Yen-Chun Lee
    • , Sumersing Patil
    •  & Herbert Waldmann

  • Article
    | Open Access

    Teixobactin is a recently identified antibiotic that shows activity against drug resistant strains of bacteria. Here, the authors report a highly convergent total synthesis of this natural product, with sufficient flexibility to also allow the synthesis of a number of analogues.

    • Kang Jin
    • , Iek Hou Sam
    •  & Xuechen Li

  • Article |

    Generating diverse structures with a minimum amount of synthetic effort is an important goal for drug discovery. Here, the authors report a two-phase synthesis for the generation of skeletally diverse small molecules—forming molecular scaffolds and subsequently diversifying each into multiple structures.

    • Miguel Garcia-Castro
    • , Lea Kremer
    •  & Kamal Kumar

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