Structure-based drug design articles within Nature Chemistry

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  • Article |

    In contrast to photothermal therapy requiring high powers over extended times and photodynamic therapy being abrogated by inhibitors of reactive oxygen species, actuation of vibronic modes in single molecules—molecular jackhammers—can now induce efficient cancer cell death. Here, the mechanical disassembly of cell membranes is characterized as the underlying mechanism by which this vibronic-driven action promotes necrotic cell death.

    • Ciceron Ayala-Orozco
    • , Diego Galvez-Aranda
    •  & James M. Tour

  • News & Views |

    It is extremely difficult to design a broad-spectrum inhibitor for metallo-β-lactamases (MBLs) due to the diversity in the active site. Now, indole-2-carboxylates have been developed as broad-spectrum inhibitors for MBLs. These inhibitors take advantage of key elements of both MBL substrates and products and work by locking a hydroxide.

    • Hongyan Li
    •  & Hongzhe Sun

  • Article |

    Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, could offer a potential route for treating Alzheimer’s disease. Now, binding sites between Aβ and LilrB2 have been discovered and computational selection has identified inhibitors that block this binding site. Cell-penetrating inhibitors were found to block the Aβ–LilrB2 interaction and limit Aβ-induced cytotoxicity.

    • Qin Cao
    • , Woo Shik Shin
    •  & Lin Jiang

  • News & Views |

    The structure of an antibiotic that is effective against Gram-positive bacteria, but not against Gram-negative bacteria, has now been modified to improve its effectiveness against Gram-negative bacteria. The approach could help broaden the spectrum of activity of other antibiotics.

    • Jed F. Fisher
    •  & Shahriar Mobashery

  • Article |

    Several natural and unnatural lissoclimide cytotoxins have been prepared via semi-synthesis and total synthesis. An X-ray co-crystal structure of chlorolissoclimide with the ribosome and evaluation of cytotoxicity and translation inhibition of new compounds in the series improves our understanding of the molecular basis for cytotoxicity.

    • Zef A. Könst
    • , Anne R. Szklarski
    •  & Christopher D. Vanderwal

  • Article |

    Structure-based drug design has generally focused on calculating binding free energies of protein–ligand complexes. It has now been shown that structural, rather than thermodynamic, stability — specifically, the work necessary to reach a quasi-bound state in which the ligand has just broken the most important contact with the receptor — can be calculated and used as a tool in virtual screening.

    • Sergio Ruiz-Carmona
    • , Peter Schmidtke
    •  & Xavier Barril

  • News & Views |

    Bicyclic peptides that are cell-permeable and can inhibit an intracellular target have been developed. These peptides consist of two rings: one enables the peptide to pass through the membrane, the other can inhibit the target.

    • Rob M. J. Liskamp

  • Article |

    Disulfide bonds formed between two cysteine residues are important in the folding and stability of proteins. Now, unnatural amino acids with side-chains that contain two thiol groups are described. Incorporation of these dithiol amino acids into a serine protease inhibitor and a nicotinic acetyl choline receptor antagonist is shown to increase their inhibitory activity.

    • Shiyu Chen
    • , Ranganath Gopalakrishnan
    •  & Christian Heinis

  • Article |

    Cascade reactions allow step-economical generation of molecular complexity. Now, a butatriene equivalent, TMSCH2C ≡ CCH2OH, is used to couple two powerful and convergent cycloadditions — the homologous Diels–Alder ([5 + 2]) and the Diels–Alder ([4 + 2]) reactions –– through a vinylogous Peterson elimination, en route to a series of kinase inhibitors inspired by staurosporine.

    • Paul A. Wender
    • , Dennis N. Fournogerakis
    •  & Magnus Pfaffenbach

  • Article |

    Light-sensitive ligands can be used to regulate neurobiological receptors with high spatiotemporal precision. Here, the optochemical control of neuronal nicotinic acetylcholine receptors, using both photoswitchable tethered agonists and antagonists, is described. These rationally designed hybrid photoreceptors will facilitate the investigation of the physiological and pathological functions of nicotinic receptors in the brain.

    • Ivan Tochitsky
    • , Matthew R. Banghart
    •  & Dirk Trauner

  • News & Views |

    Mechanical unfolding of a single DNA G-quadruplex structure with and without a stabilizing ligand can be used to calculate the binding strength of the ligand and could help to identify drugs to target these important biological assemblies.

    • Micah J. McCauley
    •  & Mark C. Williams

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