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| Open AccessGLP-1-directed NMDA receptor antagonism for obesity treatment
Unimolecular integration of NMDA receptor antagonism with GLP-1 receptor agonism effectively reverses obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease.
- Jonas Petersen
- , Mette Q. Ludwig
- & Christoffer Clemmensen
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Article |
Tuning sterol extraction kinetics yields a renal-sparing polyene antifungal
A study reports the development of a structural derivative of amphotericin B with broad antifungal activity in mice but without the renal toxicity associated with amphotericin B.
- Arun Maji
- , Corinne P. Soutar
- & Martin D. Burke
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Article
| Open AccessPredicting crystal form stability under real-world conditions
Accuracy of free-energy calculations can be improved by constructing an experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate and anhydrate crystal structures on the same energy landscape.
- Dzmitry Firaha
- , Yifei Michelle Liu
- & Marcus A. Neumann
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Article |
Carbon-to-nitrogen single-atom transmutation of azaarenes
A new type of transformation converting a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines to enable manipulation of molecular properties, is reported.
- Jisoo Woo
- , Colin Stein
- & Mark D. Levin
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Article |
Structure-based design of bitopic ligands for the µ-opioid receptor
Bitopic functionalized ligands based on fentanyl can target the sodium ion-binding site of the mu-opioid receptor and selectively modulate downstream signalling pathways, potentially leading to safer analgesics.
- Abdelfattah Faouzi
- , Haoqing Wang
- & Susruta Majumdar
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Article |
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane
The potential power of the saturated carbocycle bicyclo[3.1.1]heptane as a beneficial motif for improving the pharmacokinetic and physicochemical properties of drug candidates is demonstrated.
- Nils Frank
- , Jeremy Nugent
- & Edward A. Anderson
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Article
| Open AccessBoron clusters as broadband membrane carriers
The superchaotropic nature of globular boron cluster anions enables direct passage of a wide range of molecules across lipid membranes.
- Andrea Barba-Bon
- , Giulia Salluce
- & Werner M. Nau
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Article |
Synthesis of chiral sulfinate esters by asymmetric condensation
A synthetic strategy for the stereoselective preparation of sulfinate esters and related sulfur stereogenic centres via asymmetric condensation expands the drug discovery toolbox for these compounds.
- Xin Zhang
- , Esther Cai Xia Ang
- & Choon-Hong Tan
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Article |
A synthetic antibiotic class overcoming bacterial multidrug resistance
Structure-guided design and component-based synthesis are used to produce iboxamycin, a novel ribosome-binding antibiotic with potent activity against Gram-positive and Gram-negative bacteria.
- Matthew J. Mitcheltree
- , Amarnath Pisipati
- & Andrew G. Myers
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Article |
Rational design of a new antibiotic class for drug-resistant infections
A lead-optimization strategy combining porin permeation properties and biochemical potency leads to development of a new class of antibiotic based on broad inhibition of penicillin-binding proteins from Gram-negative bacteria.
- Thomas F. Durand-Reville
- , Alita A. Miller
- & Ruben A. Tommasi
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Article |
RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance
A class of compounds with a dual mechanism of action—direct targeting of IspH and stimulation of cytotoxic γδ T cells to enhance pathogen clearance—are active against multidrug-resistant bacteria.
- Kumar Sachin Singh
- , Rishabh Sharma
- & Farokh Dotiwala
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Article |
A non-hallucinogenic psychedelic analogue with therapeutic potential
Psychedelic alkaloids served as lead structures for the development of tabernanthalog, a non-hallucinogenic and non-toxic analogue that reduces alcohol- and heroin-seeking behaviour and produces antidepressant-like effects in rodents.
- Lindsay P. Cameron
- , Robert J. Tombari
- & David E. Olson
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Article |
Synthetic group A streptogramin antibiotics that overcome Vat resistance
Modular synthesis and structural biology are used to design and characterize group A streptogramin antibiotics, one of which has activity against streptogramin-resistant strains and demonstrates efficacy in a mouse model of bacterial infection.
- Qi Li
- , Jenna Pellegrino
- & Ian B. Seiple
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Article |
Clinical targeting of HIV capsid protein with a long-acting small molecule
The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.
- John O. Link
- , Martin S. Rhee
- & Tomas Cihlar
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Article |
Preparation of cyclohexene isotopologues and stereoisotopomers from benzene
Cyclohexene isotopologues and stereoisotopomers with varying degrees of deuteration are formed by binding a tungsten complex to benzene, which facilitates the selective incorporation of deuterium into any position on the ring.
- Jacob A. Smith
- , Katy B. Wilson
- & W. Dean Harman
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Article |
Late-stage oxidative C(sp3)–H methylation
A manganese-catalysed oxidative C(sp3)–H methylation method allows a methyl group to be selectively installed into medicinally important heterocycles, providing a way to improve pharmaceuticals and better understand the ‘magic methyl effect’.
- Kaibo Feng
- , Raundi E. Quevedo
- & M. Christina White
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Article |
HBO1 is required for the maintenance of leukaemia stem cells
The MYST acetyltransferase HBO1 is a critical regulator in maintaining leukaemia stem cells, and a small-molecule inhibitor of HBO1 is developed that shows efficacy against a range of acute myeloid leukaemia cells.
- Laura MacPherson
- , Juliana Anokye
- & Mark A. Dawson
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Article |
Structural basis of species-selective antagonist binding to the succinate receptor
High-resolution crystal structures of the rat succinate receptor SUCNR1 in an inactive confirmation, and the humanized rat SUCNR1 bound to an antagonist, provide insights into the structure of these receptors and the species selectivity of antagonist binding.
- Matthias Haffke
- , Dominique Fehlmann
- & Veli-Pekka Jaakola
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Article |
Chimeric peptidomimetic antibiotics against Gram-negative bacteria
A class of chimeric synthetic antibiotics that bind to lipopolysaccharide and BamA shows potent activity against multidrug-resistant Gram-negative bacteria, with the potential to address life-threatening infections.
- Anatol Luther
- , Matthias Urfer
- & Daniel Obrecht
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Letter |
Modular click chemistry libraries for functional screens using a diazotizing reagent
A ‘click’ reaction is developed for the simple and rapid formation of azides from primary amines, and is used to prepare a library of over 1,200 azides for subsequent use in the existing triazole annulation click reaction.
- Genyi Meng
- , Taijie Guo
- & Jiajia Dong
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Letter |
Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas
N-trifluoromethyl analogues of amides and related carbonyl compounds are prepared via bench-stable carbamoyl fluoride building blocks.
- Thomas Scattolin
- , Samir Bouayad-Gervais
- & Franziska Schoenebeck
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Article |
Ultra-large library docking for discovering new chemotypes
Using a make-on-demand library that contains hundreds-of-millions of molecules, structure-based docking was used to identify compounds that, after synthesis and testing, are shown to interact with AmpC β-lactamase and the D4 dopamine receptor with high affinity.
- Jiankun Lyu
- , Sheng Wang
- & John J. Irwin
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Letter |
Design of amidobenzimidazole STING receptor agonists with systemic activity
A small-molecule agonist for the cGAS–STING pathway has systemic activity in a mouse model of colon cancer.
- Joshi M. Ramanjulu
- , G. Scott Pesiridis
- & John Bertin
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Article |
Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis
A series of compounds are discovered for the treatment of visceral leishmaniasis, and cdc2-related kinase 12 (CRK12) is identified as the probable primary drug target.
- Susan Wyllie
- , Michael Thomas
- & Ian H. Gilbert
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Letter |
Nanoscale synthesis and affinity ranking
A system that combines nanoscale synthesis and affinity ranking enables high-throughput screening of reaction conditions and bioactivity for a given protein target, accelerating the process of drug discovery.
- Nathan J. Gesmundo
- , Bérengère Sauvagnat
- & Tim Cernak
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Article |
Molecular basis of USP7 inhibition by selective small-molecule inhibitors
Small molecules are identified that inhibit the ubiquitin-specific protease USP7 with high affinity and specificity as explained by co-crystal structures, and are shown to reduce tumour growth in mice.
- Andrew P. Turnbull
- , Stephanos Ioannidis
- & David Komander
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Letter |
Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure
The authors report the crystal structure of the β2 adrenergic receptor in complex with compound 15, an allosteric modulator that binds to an alternative binding pocket.
- Xiangyu Liu
- , Seungkirl Ahn
- & Brian K. Kobilka
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Letter |
Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity
A vaccine-driven approach shows that the prominent stimulant features of the psychoactive profile of fenethylline can be attributed to amphetamine, with synergistic support from theophylline, and no direct contributions from the parent drug molecule.
- Cody J. Wenthur
- , Bin Zhou
- & Kim D. Janda
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Letter |
Crystal structures of agonist-bound human cannabinoid receptor CB1
Crystal structures of the human cannabinoid receptor 1 (CB1) bound to the agonists AM11542 and AM841 reveal notable structural rearrangements upon receptor activation, and this flexibility may be a common feature among other G-protein-coupled receptors.
- Tian Hua
- , Kiran Vemuri
- & Zhi-Jie Liu
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Article |
Structural basis for selectivity and diversity in angiotensin II receptors
Crystal structures of two complexes of the angiotensin II receptor AT2R with distinct tightly bound ligands reveal an active-like state of the receptor, in which helix VIII adopts a non-canonical position that blocks binding of G proteins and β-arrestins.
- Haitao Zhang
- , Gye Won Han
- & Vadim Cherezov
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Letter |
Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists
The crystal structure of CCR2 chemokine receptor in a complex with two different antagonists—one orthosteric the other allosteric—which functionally cooperate to inhibit CCR2.
- Yi Zheng
- , Ling Qin
- & Tracy M. Handel
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Career Brief |
Big pharma: UK drugs outsourced
United Kingdom has cut drug-development research jobs over past decade.
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Article |
Diversity-oriented synthesis yields novel multistage antimalarial inhibitors
The bicyclic azetidines, a class of potent, well-tolerated antimalarial compounds that is active against multiple stages of the Plasmodium life-cycle, has been discovered following screens against libraries of compounds reminiscent of natural products.
- Nobutaka Kato
- , Eamon Comer
- & Stuart L. Schreiber
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Letter |
Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness
A selective inhibitor of the kinetoplastid proteasome (GNF6702) is identified that is highly efficacious in vivo, clearing the parasites that cause leishmaniasis, Chagas disease and sleeping sickness from mice, highlighting the possibility of developing a single class of drugs for these neglected diseases.
- Shilpi Khare
- , Advait S. Nagle
- & Frantisek Supek
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Inside View |
Inside View: Astrazeneca
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Article |
A novel multiple-stage antimalarial agent that inhibits protein synthesis
The description of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of Plasmodium falciparum and good pharmacokinetic and safety properties, with potential for single-dose treatment, chemoprotection and prevention of transmission.
- Beatriz Baragaña
- , Irene Hallyburton
- & Ian H. Gilbert
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Outlook |
Nanotechnology: Deliver on a promise
Effective treatment of cancer requires getting the drugs precisely to the target. Enter the nanoparticle.
- Jessica Wright
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Outlook |
Clinical trials: More trials, fewer tribulations
Clinical studies that group patients according to their molecular profile can make for better and faster drug approval decisions.
- Michael Eisenstein
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Article |
Automated design of ligands to polypharmacological profiles
An automated approach designing drug ligands to multi-target profiles (with a 75% prediction success rate) is experimentally validated by the invention of novel ligands tailored to the complex and physiologically-relevant goal of identifying drugs that can specifically target profiles of multiple proteins.
- Jérémy Besnard
- , Gian Filippo Ruda
- & Andrew L. Hopkins
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Article |
High-resolution crystal structure of human protease-activated receptor 1
The X-ray crystal structure of the human G-protein-coupled receptor protease-activated receptor 1 (PAR1) bound to the antagonist vorapaxar is solved, revealing an unusual method of drug binding that should facilitate the development of improved PAR1-selective antagonists.
- Cheng Zhang
- , Yoga Srinivasan
- & Brian K. Kobilka
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News & Views |
Toolkit of reagents to aid drug discovery
Reagents have been developed that allow carbon—hydrogen bonds on benzene-like compounds called heterocycles to be converted directly into carbon—carbon bonds. The finding will be a boon to medicinal chemists. See Letter p.95
- William J. Pitts
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News & Views |
Snapshot of an activated peptide receptor
Developing therapeutic drugs that target peptide receptors is challenging. The structure of one of these G-protein-coupled receptors, NTS1, activated and bound to a peptide, provides an excellent starting point. See Article p.508
- Felix Hausch
- & Florian Holsboer
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Research Highlights |
Fragile-X drug in humans and mice
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Outlook |
Therapeutics: Strength in numbers
Several new drugs for treating chronic obstructive pulmonary disease are about to hit the market, with more in the pipeline.
- Duncan Graham-Rowe
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News & Views |
A biochemical messenger made easily
Biochemicals known as prostaglandins are challenging targets for synthetic organic chemistry. Yet by channelling the reactivity of a simple reactant, a powerful synthesis of one such compound has been achieved. See Letter p.278
- Erik J. Sorensen
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News |
Alzheimer’s drugs take a new tack
Hopes pinned on pre-emptive clinical trials after latest setbacks.
- Ewen Callaway
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Editorial |
Take a stand
Legal actions and oversight are necessary to keep the drug industry in line.
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Letter |
Activation of remote meta-C–H bonds assisted by an end-on template
Rapid synthesis of complex molecules via selective functionalization of unactivated carbon–hydrogen bonds is here made easier with the use of removable ‘templates’ that enable the activation of distal bonds.
- Dasheng Leow
- , Gang Li
- & Jin-Quan Yu
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News |
Model pigs face messy path
As approvals for engineered food animals stall, pigs may be US regulators’ next challenge.
- Amy Maxmen