Screening articles within Nature Chemistry

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  • Research Briefing |

    A protein-templated selection approach has been developed for the discovery of full ligands from dual-pharmacophore DNA-encoded libraries by incorporating fragment linking into the selection process. The performance of this method was demonstrated with selections against protein–protein interaction and protein–DNA interaction targets, through which potent and selective inhibitors were identified.

  • Article |

    Dual-pharmacophore DNA-encoded chemical libraries enable the identification of two synergistic binders for a biological target, but subsequent linking of this pair is required to obtain a full ligand, which can be challenging. Here we report a protein-templated selection of DNA-encoded dynamic library that can identify full ligands from fragment libraries without the need for subsequent fragment linking.

    • Yu Zhou
    • , Wenyin Shen
    •  & Xiaoyu Li

  • 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

  • Article |

    Acylhydrazones are often found in compounds across screening databases, and numerous bioactive acylhydrazones exist. This functional group can isomerize between E and Z in response to light or upon exposure to thiols. Now, E/Z isomerization is found to impact activities of bioactive acylhydrazones and should be routinely analysed.

    • Zhiwei Zhang
    • , Giang N. T. Le
    •  & G. Andrew Woolley

  • Article |

    DNA-encoded libraries facilitate the discovery of ligands that interact with biomolecules but such technologies do not take full advantage of the principles of Darwinian selection. Now, libraries of conformationally constrained peptides (Dsuprabodies) have been assembled using a strategy that allows for iterative cycles of selection, amplification and diversification. This method was validated with selections against streptavidin and PD-L1.

    • Balayeshwanth R. Vummidi
    • , Lluc Farrera-Soler
    •  & Nicolas Winssinger

  • 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

  • Article |

    Cyclic β-amino acids can add useful properties to peptides, such as inducing turn structures or providing resistance to proteases. To harness these properties up to ten consecutive cyclic β-amino acids have now been ribosomally incorporated via genetic code reprogramming into a foldamer peptide library that has been screened for potent binders against a protein target, human factor XIIa.

    • Takayuki Katoh
    • , Toru Sengoku
    •  & Hiroaki Suga

  • News & Views |

    Biological receptors distinguish between S- and R-enantiomers and these subtle differences in chirality can lead to vastly different protein affinities. Now, a proteomics approach has been developed that capitalizes on chirality to map enantiomeric probe pairs and provides a rapid and global view of protein ligandability within the cell.

    • Yuka Amako
    •  & Christina M. Woo

  • Article |

    A set of enantioprobes—photoreactive, clickable fragment pairs differing only in absolute stereochemistry—have been used to provide a robust and streamlined chemical proteomic map of small-molecule/protein interactions in human cells. More than 170 stereoselective fragment–protein interactions were discovered and shown to occur at functional sites on proteins from diverse classes.

    • Yujia Wang
    • , Melissa M. Dix
    •  & Benjamin F. Cravatt

  • 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 |

    An artificial aldolase has been optimized using an ultrahigh-throughput microfluidic screening assay. The evolved enzyme exhibits excellent stereoselectivity and broad substrate scope. Structural studies suggest that a Lys-Tyr-Asn-Tyr catalytic tetrad, which emerged during directed evolution, is responsible for the >109 rate enhancement achieved by this catalyst.

    • Richard Obexer
    • , Alexei Godina
    •  & Donald Hilvert

  • 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 |

    Copper is a transition metal ion essential for the regulation of cellular oxidative stress and ATP production. Now, the inhibition of copper-trafficking proteins by a small molecule has been shown to significantly reduce proliferation of cancer cells. The results indicate that copper-trafficking proteins could represent new anti-tumour therapeutic targets.

    • Jing Wang
    • , Cheng Luo
    •  & Chuan He

  • Article |

    It is difficult to develop a selective ligand for point mutations in proteins that are not found in easily addressable locations. Now, an all-chemical, epitope-targeting strategy has been reported, and was used to discover an inhibitory peptide with selectivity for the E17K point mutation in the PH Domain of the Akt1 oncoprotein.

    • Kaycie M. Deyle
    • , Blake Farrow
    •  & James R. Heath

  • Article |

    A method for rapidly screening small-molecule inhibitors of amyloid assembly has been developed. This method uses electrospray ionization–ion mobility spectrometry–mass spectrometry to detect and identify the type of inhibition. A screen of this nature could help in the discovery of therapeutics for numerous diseases associated with aberrant protein aggregation.

    • Lydia M. Young
    • , Janet C. Saunders
    •  & Alison E. Ashcroft

  • Interview |

    Adam Nelson and Stuart Warriner, from the University of Leeds, talk with Nature Chemistry about their work to develop viable synthetic strategies for preparing new chemical structures in parallel with the identification of desirable biological activity.

    • Stephen Davey

  • Article |

    A discovery approach termed activity-directed synthesis is described; it exploits arrays of reactions whose outcome is critically dependent on the conditions used, and prioritizes reactions that yield bioactive product mixtures. The discovery of both bioactive small molecules and associated synthetic routes thus occurs in parallel.

    • George Karageorgis
    • , Stuart Warriner
    •  & Adam Nelson

  • Article |

    Directed evolution has emerged as a powerful tool for the identification of improved enzyme catalysts. Now, gel-shell beads are introduced as compartments that cage an enzyme with its encoding DNA, constituting a new genotype–phenotype linkage. Screening of 107 gel-shell beads by flow cytometry leads to an improved phosphotriesterase bioremediation catalyst.

    • Martin Fischlechner
    • , Yolanda Schaerli
    •  & Florian Hollfelder

  • Article |

    The adoption of multiple conformations by proteins presents a challenge for ligand discovery using docking simulations. Now, a method for representing the conformational behaviour of a flexible protein in docking screens, which is guided by experimental crystallography data, is shown to predict protein conformation, ligand pose and aid the discovery of new ligands.

    • Marcus Fischer
    • , Ryan G. Coleman
    •  & Brian K. Shoichet

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