Drug discovery and development articles within Nature Communications

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  • 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

    Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (Mpro). Here, the authors co-crystallised Mpro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.

    • Kangsa Amporndanai
    • , Xiaoli Meng
    •  & S. Samar Hasnain

  • 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

    Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here, the authors generate single-drug nanoparticles by hybridising lysomotropic detergents and the bisaminoquinoline-based autophagy inhibitor, and show their therapeutic potential as autophagy-inhibition based combination therapy.

    • Zhao Ma
    • , Jin Li
    •  & Yuanpei Li

  • Article
    | Open Access

    The natural antibiotic teixobactin kills bacteria by direct binding to their cognate cell wall precursors (Lipid II and III). Here authors use solid-state NMR to reveal the native binding mode of teixobactins and show that teixobactins only weakly bind to Lipid II in anionic cellular membranes.

    • Rhythm Shukla
    • , João Medeiros-Silva
    •  & Markus Weingarth

  • Article
    | Open Access

    Selective C-H trifluoromethoxylation of pyridines remains a formidable synthetic challenge. Here, the authors report a silver-mediated late-stage C-H trifluoromethoxylation of arenes and heteroarenes as limiting reagents with trifluoromethoxide anion.

    • Zhijie Deng
    • , Mingxin Zhao
    •  & Pingping Tang

  • 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

    While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.

    • James O’Connell
    • , John Porter
    •  & Alastair Lawson

  • Article
    | Open Access

    The Aza Paternò-Büchi reaction is arguably among the most direct approaches to functionalized azetidines, which are common medicinal scaffolds. Here, the authors report a mild and selective visible light-enabled intramolecular aza Paternò-Büchi reaction yielding bicyclic azetidines in high yields and diastereoselectivity.

    • Marc R. Becker
    • , Alistair D. Richardson
    •  & Corinna S. Schindler

  • Article
    | Open Access

    The peptide hormone GLP-1 has the potential to be a remedy for diabetes type II, yet is unstable. Here, the authors synthesized α-peptide-oligourea hybrid analogues of GLP-1 some of which showing significantly prolonged activity in vivo.

    • Juliette Fremaux
    • , Claire Venin
    •  & Sébastien R. Goudreau

  • Article
    | Open Access

    High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

    • Adriana E. Tron
    • , Matthew A. Belmonte
    •  & Alexander W. Hird

  • Article
    | Open Access

    Mutations in pantotenate kinase (PANK) cause neurodegneration. Here the authors carry out achemical screen and identify a PANK activator that is orally available, crosses the blood brain barrierand show that it effecttive in improving pathology and life span in a mouse model of the disease.

    • Lalit Kumar Sharma
    • , Chitra Subramanian
    •  & Suzanne Jackowski

  • Article
    | Open Access

    Aberrant mTORC1 signaling is linked to several chronic diseases. Here, the authors develop a small molecule inhibitor that binds the small G-protein Rheb and selectively blocks mTORC1 signaling, holding potential for therapeutic applications.

    • Sarah J. Mahoney
    • , Sridhar Narayan
    •  & Eddine Saiah

  • Article
    | Open Access

    NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.

    • Brent D. G. Page
    • , Nicholas C. K. Valerie
    •  & Thomas Helleday

  • Article
    | Open Access

    The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.

    • Mark A. T. Blaskovich
    • , Karl A. Hansford
    •  & Matthew A. Cooper

  • Article
    | Open Access

    A substantial obstacle in basic research is the use of poorly validated tool compounds with purported useful biological functions. Here, the authors systematically profile widely used histone acetyltransferase inhibitors and find that the majority are nonselective interference compounds.

    • Jayme L. Dahlin
    • , Kathryn M. Nelson
    •  & Michael A. Walters

  • Article
    | Open Access

    Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.

    • David A. Baker
    • , Lindsay B. Stewart
    •  & Simon A. Osborne

  • Article
    | Open Access

    Epigenetic drugs are emerging as a powerful therapeutic option for cancer treatment. Here, the authors synthesized selective chemical probes that simultaneously inhibit the G9a and DNMTs methyltransferase activity and demonstrate their anti-tumour activity usingin vitro and in vivomodels of haematological neoplasia.

    • Edurne San José-Enériz
    • , Xabier Agirre
    •  & Felipe Prosper

  • Article
    | Open Access

    Allostery and drug-drug synergism can yield potential novel therapies with existing molecules. Here, the authors provide evidence that two unrelated drugs have increased cytotoxicity in cancer cells, which coincides with increased formation of chromatin adducts.

    • Zenita Adhireksan
    • , Giulia Palermo
    •  & Curt A. Davey

  • Article
    | Open Access

    Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.

    • Chang Seok Lee
    • , Amy D. Hanna
    •  & Susan L. Hamilton

  • Article
    | Open Access

    Drug resistant tuberculosis (TB) infections are emerging at a high rate, with only few therapeutic options currently available. Here, the authors report synthetic analogues of the natural product sansanmycin that target mycobacterial cell wall biosynthesis and represent potent leads for improved anti-TB treatments.

    • Anh T. Tran
    • , Emma E. Watson
    •  & Richard J. Payne

  • Article
    | Open Access

    Traditional inflammation and pain relief drugs target both cyclooxygenase 1 and 2 (COX-1 and COX-2), causing severe side effects. Here, the authors use in situ click chemistry to develop COX-2 specific inhibitors with high in vivo anti-inflammatory activity.

    • Atul Bhardwaj
    • , Jatinder Kaur
    •  & Frank Wuest

  • Article
    | Open Access

    Steroid units can facilitate membrane permeation and bioavailability in drugs. Here, using a medicinal chemistry program, Krieget al. identify an arylmethylamino steroid that kills Plasmodium parasites, likely through a chelate-based quinone methide mechanism, and has activity against Schistosoma mansoni.

    • Reimar Krieg
    • , Esther Jortzik
    •  & Katja Becker

  • Article
    | Open Access

    Molecular fragments are useful tools in drug-discovery but they might be hard to identify due to their weak affinity to the targets. Here, the authors use a protein-templated assembly to design high affinity inhibitors of Coxsackie virus 3C protease, a pharmacological target against enteroviral infections.

    • Daniel Becker
    • , Zuzanna Kaczmarska
    •  & Jörg Rademann

  • Article
    | Open Access

    G protein-coupled receptors (GPCRs) are involved in key signalling pathways and represent important targets for the treatment of neurological and psychiatric disorders. Here, the authors describe powerful bivalent ligands that efficiently bind to therapeutically relevant GPCR heterodimers

    • Harald Hübner
    • , Tamara Schellhorn
    •  & Peter Gmeiner

  • Article
    | Open Access

    Noscapine is a potential anticancer drug that is traditionally isolated from the opium poppy Papaver somniferum. Here, Li and Smolke reconstitute the noscapine gene cluster in Saccharomyces cerevisiae, to achieve the microbial production of noscapine and related pathway intermediates, and provide new insights into the biosynthesis of noscapine.

    • Yanran Li
    •  & Christina D. Smolke

  • Article
    | Open Access

    The conformational dynamics of a compound has a large effect on ligand/receptor binding. Here, the authors employ NMR spectroscopy to study ligand binding to the enzyme LpxC, discovering an inhibitor envelope that was not identifiable by crystallography and subsequently developing a highly potent inhibitor.

    • Chul-Jin Lee
    • , Xiaofei Liang
    •  & Pei Zhou

  • Article
    | Open Access

    The availability of high-yield virus strains remains an important bottleneck in the rapid production of influenza vaccines. Here, the authors report the development of influenza A vaccine backbone that improves the virus yield of various seasonal and pandemic influenza vaccine strains in cell culture.

    • Jihui Ping
    • , Tiago J.S. Lopes
    •  & Yoshihiro Kawaoka

  • Article
    | Open Access

    The biological properties of dendrimers are thought to be largely dependent on the chemical nature of their surface. Here, the authors show that the internal scaffold of dendritic nanodrugs strongly influences their bioactivity, based on convergent information from biology and computation results.

    • Anne-Marie Caminade
    • , Séverine Fruchon
    •  & Rémy Poupot

  • Article
    | Open Access

    Screening for new anthelmintic compounds that are active against parasitic nematodes is costly and labour intensive. Here, the authors use the non-parasitic nematode Caenorhabditis elegansto identify 30 anthelmintic lead compounds in an effective and cost-efficient manner.

    • Andrew R. Burns
    • , Genna M. Luciani
    •  & Peter J. Roy

  • Article
    | Open Access

    Organometallic complexes are effective hydrogenation catalysts for organic reactions. Here the authors report for the first time that transfer hydrogenation catalysis can take place inside the cell and could be used as a novel anticancer strategy.

    • Joan J. Soldevila-Barreda
    • , Isolda Romero-Canelón
    •  & Peter J. Sadler

  • Article
    | Open Access

    Ruthenium-cymene-based compounds are investigated as potential anticancer drugs. Here, Adhireksan et al.study two ruthenium-containing compounds with varying cytotoxicity and show that differences in ligand structure may explain their activity and binding to different subcellular targets.

    • Zenita Adhireksan
    • , Gabriela E. Davey
    •  & Curt A. Davey

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