Chemical libraries articles within Nature Chemistry

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  • Article
    | Open Access

    Design strategies that possess both biological relevance and structural diversity may lead to compound collections that are enriched in diverse bioactivities. Now a diverse pseudo-natural product design principle has been established to efficiently explore biologically relevant chemical space. Through dearomatization reactions, a compound collection enriched in both structural and biological diversity was rapidly generated.

    • Sukdev Bag
    • , Jie Liu
    •  & Herbert Waldmann

  • Article |

    The design and construction of a stereo-defined DNA-encoded chemical library, featuring the four different 4-amino-proline stereoisomers as a central scaffold, has now enabled the discovery of potent ligands to proteins of pharmaceutical interest. Parallel screening with closely related isoforms (anti-targets) facilitated the isolation of hits with high selectivity ratios.

    • Sebastian Oehler
    • , Laura Lucaroni
    •  & Gabriele Bassi

  • Perspective |

    DNA-encoded libraries can be applied in a diverse range of applications beyond simple binding assays. This Perspective covers the recent progress in using DNA-encoded chemical libraries to investigate complex biological targets and discusses their potential to identify structures that elicit function or possess other useful properties.

    • Yiran Huang
    • , Yizhou Li
    •  & Xiaoyu Li

  • News & Views |

    Aryl aminooxetanes are used as amide bioisosteres in drug discovery but there are limited strategies for synthesizing them. Now, an approach has been developed that simplifies the synthesis of these privileged motifs, enabling a broad range of amines to be used.

    • Malcolm P. Huestis
    •  & Jack A. Terrett

  • Article |

    Sulfonyl fluorides typically react with nucleophiles exclusively at sulfur, leading to the substitution of fluoride, as is the case in SuFEx reactions. Now, an alternative defluorosulfonylative reaction has been developed, coupling 3-aryloxetane sulfonyl fluorides with amines to generate amino-oxetanes. The mild conditions and high functional group tolerance enable the preparation of oxetane analogues of benzamide drugs via oxetane carbocation intermediates.

    • Juan J. Rojas
    • , Rosemary A. Croft
    •  & James A. Bull

  • Article |

    A method to label membrane proteins with a DNA tag has been developed that enables the selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. As a demonstration, a 30-million-compound DNA-encoded chemical library is screened against folate receptor, carbonic anhydrase 12 and epidermal growth factor receptor on live cells.

    • Yiran Huang
    • , Ling Meng
    •  & Xiaoyu Li

  • Perspective |

    The structures of biologically active natural products have long served as inspiration in drug discovery. This Perspective outlines design principles and connectivity patterns for the de novo combination of natural product-derived fragments. The resulting ‘pseudo-natural products’ retain biological relevance yet exhibit structures and bioactivities not found in the natural products and their derivatives.

    • George Karageorgis
    • , Daniel J. Foley
    •  & Herbert Waldmann

  • Article |

    Modulating particular ubiquitin chains using binding molecules is challenging given the diversity of chain lengths and linkages found in vivo. Now, tight binding modulators that are specific to K48-linked ubiquitin chains have been found by combining protein synthesis and screening of macrocyclic peptide ligands.

    • Mickal Nawatha
    • , Joseph M. Rogers
    •  & Ashraf Brik

  • News & Views |

    Methods for generating molecular diversity provide a route to screen a wider section of chemical space, to discover compounds with useful biological properties. Now, a complexity-to-diversity strategy has enabled the discovery of a multi-cyclic structure from a complex natural product that induces ferroptotic cell death in cancer cells.

    • Tatiana Cañeque
    •  & Raphaël Rodriguez

  • Article |

    A set of stereochemically complex and structurally diverse compounds were created from the diterpene natural product pleuromutilin using the complexity-to-diversity strategy. Phenotypic screening identified a compound that induces rapid ferroptotic death of cancer cells. Experiments to probe the mechanism revealed the compound to be an inhibitor of thioredoxin.

    • Evijola Llabani
    • , Robert W. Hicklin
    •  & Paul J. Hergenrother

  • Article |

    Rapamycin and FK506 are macrocycles that contain an FKBP-binding domain and an effector domain responsible for interacting with their respective targets, mTOR and calcineurin. Now, a 45,000-compound macrocycle library has been synthesized by fusing oligopeptides with synthetic FKBP-binding domains. Screening and subsequent optimization yielded a highly potent FKBP-dependent inhibitor of hENT1.

    • Zufeng Guo
    • , Sam Y. Hong
    •  & Jun O. Liu

  • Editorial |

    Encoded chemical libraries can be used to screen a vast array of compounds against a protein target to identify potent binders. A collection of articles in this issue discuss different methods to increase the chemical space sampled by encoded macrocycle libraries and the advantages that such libraries offer for discovering new drug leads.

  • Q&A |

    Ghotas Evindar, Chemistry Group Leader at GlaxoSmithKline, talks with Nature Chemistry about the advantages of using encoded libraries in drug discovery and the challenges these technologies present.

    • Russell Johnson

  • News & Views |

    Certain drug targets have been deemed undruggable because of the difficulty in finding pharmacologically useful inhibitors. Now, two teams have developed exciting technologies for the creation of diverse collections of macrocyclic molecules and have demonstrated their usefulness for discovering macrocyclic inhibitors.

    • Emil S. Iqbal
    •  & Matthew C. T. Hartman

  • Article |

    Crosslinking within peptides containing two pairs of cysteines to form chemical bridges has now been shown to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Applying this strategy to phage-encoded libraries yielded binders with remarkable affinities despite the small molecular mass.

    • Sangram S. Kale
    • , Camille Villequey
    •  & Christian Heinis

  • Article |

    A second-generation DNA-templated library of 256,000 small-molecule macrocycles has been developed. The improved method was created by streamlining and integrating multiple aspects of DNA-encoded and DNA-templated library synthesis methodology. In vitro selection of the macrocycle library against insulin-degrading enzyme enabled the discovery of potent inhibitors.

    • Dmitry L. Usanov
    • , Alix I. Chan
    •  & David R. Liu

  • Article |

    Pharmaceutical compound libraries are an essential part of drug discovery and the screening of libraries for new drug leads is routine. It has now been shown that these heterocycle-rich, diverse libraries can also be used for ligand discovery. The discovery and application of several new ligands to nickel-catalysed cross-electrophile coupling is demonstrated.

    • Eric C. Hansen
    • , Dylan J. Pedro
    •  & Daniel J. Weix

  • Article |

    A method to identify pairs of ligands that simultaneously bind to a target protein has been developed. The method uses two DNA-encoded chemical sub-libraries that self-assemble to form stable dual-display structures, and an encoding system that can be decoded by DNA sequencing and enables both ligands to be identified.

    • Moreno Wichert
    • , Nikolaus Krall
    •  & Jörg Scheuermann

  • Interview |

    Jeffrey Bode from ETH Zürich talks with Nature Chemistry about his group's work on synthetic fermentation, and how he hopes it could bring the power of chemical synthesis into the hands of citizen scientists.

    • Stephen Davey

  • News & Views |

    The generation of chemical libraries for screening is a key part of the drug discovery process. Now, two studies describe attempts to combine features of natural product biosynthesis into the creation of libraries with the aim of mimicking nature's success at the production of bioactive molecules.

    • Derek B. Lowe

  • Article |

    The production of biologically active compounds by microbial fermentation has proved highly successful in drug discovery. Now, a method that mimics this process has been used to prepare unnatural peptides from small building blocks without the need for additional reagents, and in a fashion that is immediately compatible with biological screening.

    • Yi-Lin Huang
    •  & Jeffrey W. Bode

  • News & Views |

    A synthetic strategy that uses a series of simple reactions to distort the core architecture of complex natural products could provide libraries of stereochemically rich compounds that will help in the search for new biological probes and drugs.

    • Indrajeet Sharma
    •  & Derek S. Tan

  • News & Views |

    The design of a small-molecule library for drug discovery attempts to combine the favourable diversity of natural product structures with the modularity of peptide synthesis.

    • Jeffrey Aubé

  • Article |

    A 16-member diastereoisomer library known to contain macrosphelides A and E is synthesized as a mixture with the aid of a new encoding strategy for fluorous mixture synthesis. A simple process of sequential demixing and tag removal provides each of the isomers in individual, pure form. Analysis of the other library members ultimately leads to a structural reassignment for macrosphelide D.

    • Dennis P. Curran
    • , Mantosh K. Sinha
    •  & Dae-Hyun Cho

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