Featured
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| Open AccessDesign of target specific peptide inhibitors using generative deep learning and molecular dynamics simulations
Here the authors report a computational approach which integrates deep learning and structural modelling to design target-specific peptides. They apply this to β-catenin and NF-κB essential modulator, resulting in improved binding, highlighting the efficacy of this strategy.
- Sijie Chen
- , Tong Lin
- & Xiaolin Cheng
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Perspective
| Open AccessAnnexins—a family of proteins with distinctive tastes for cell signaling and membrane dynamics
Annexins are calcium-regulated membrane binding proteins with an array of cellular activities. Here, Gerke et al. describe recent research highlighting the many functions of annexins and provide a view on directions for the future.
- Volker Gerke
- , Felicity N. E. Gavins
- & Ursula Rescher
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Article
| Open AccessStructure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open AccessLearning representations for image-based profiling of perturbations
Assessing cell phenotypes in image-based assays requires solid computational methods for transforming images into quantitative data. Here, the authors present a strategy for learning representations of treatment effects from high-throughput imaging, following a causal interpretation.
- Nikita Moshkov
- , Michael Bornholdt
- & Juan C. Caicedo
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Article
| Open AccessStructural optimization of siRNA conjugates for albumin binding achieves effective MCL1-directed cancer therapy
Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.
- Ella N. Hoogenboezem
- , Shrusti S. Patel
- & Craig L. Duvall
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Article
| Open AccessCepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery
Cepharanthine is a secondary metabolite isolated from Stephania with a variety of medicinal properties. Here, the authors assembled three Stephania genomes, propose cepharanthine biosynthetic pathway, and assess the antiviral potential of cepharanthine-related metabolites.
- Liang Leng
- , Zhichao Xu
- & Shilin Chen
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Article
| Open AccessCyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy
Pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL are the targets of anti-tumour drugs, but resistance is emerging. The authors present cyclic peptides against BCL-2 and BCL-XL, with a distinct mechanism of targeting characterised.
- Fengwei Li
- , Junjie Liu
- & Dalei Wu
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Article
| Open AccessLeukemic stem cells activate lineage inappropriate signalling pathways to promote their growth
In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type.
- Sophie G. Kellaway
- , Sandeep Potluri
- & Constanze Bonifer
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Article
| Open AccessModeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.
- Thomas L. Maurissen
- , Alena J. Spielmann
- & Héloïse Ragelle
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Article
| Open AccessDrug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor
There is a need for effective antiviral drugs against RSV infection. Conducting an RSV repurposing screen using the ReFRAME library Sake et al. identify lonafarnib as an RSV fusion protein inhibitor, characterize its binding site within the viral protein and show its antiviral effects in a mouse model.
- Svenja M. Sake
- , Xiaoyu Zhang
- & Thomas Pietschmann
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Article
| Open AccessStructural basis for lysophosphatidylserine recognition by GPR34
GPR34 is a GPCR which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative endogenous ligand. Here, authors report two cryo-EM structures of human GPR34-Gi complex with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or its derivative M1.
- Tamaki Izume
- , Ryo Kawahara
- & Osamu Nureki
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Article
| Open AccessRegulating protein corona on nanovesicles by glycosylated polyhydroxy polymer modification for efficient drug delivery
The dynamic protein corona hinders the uptake of nanocarriers in desired target cell populations, limiting their bench-to-bedside translation. Here the authors reveal that the modification of hydroxyl and amino functional groups on nanovesicles can rationally regulate the composition of protein coronas to improve the efficiency of targeted drug delivery.
- Yunqiu Miao
- , Lijun Li
- & Yong Gan
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Article
| Open AccessAntiviral fibrils of self-assembled peptides with tunable compositions
In this work, the authors report the use of a computationally and rationally designed self-assembling peptide that has robust antiviral capability with demonstrated specificity in binding to SARS-CoV-2 and inhibition of viral entry into human cells.
- Joseph Dodd-o
- , Abhishek Roy
- & Vivek Kumar
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Article
| Open AccessAAV-delivered muscone-induced transgene system for treating chronic diseases in mice via inhalation
Long-term control of therapeutic transgene expression is needed. Here the authors report a muscone-induced transgene system packaged into AAVs based on a G protein-coupled murine olfactory receptor and a synthetic cAMP-responsive promoter: they show dose- and exposure-time-dependent gene expression control in mice.
- Xin Wu
- , Yuanhuan Yu
- & Haifeng Ye
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Article
| Open AccessDynamicBind: predicting ligand-specific protein-ligand complex structure with a deep equivariant generative model
Proteins often function by changing conformations upon ligand binding. Efficient structural modelling of these interactions, crucial for drug discovery, is limited: here the authors address this with DynamicBind, a diffusion-based deep generative model.
- Wei Lu
- , Jixian Zhang
- & Shuangjia Zheng
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Article
| Open AccessCDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver
Obesity is a risk factor for diseases. Here, authors found that inhibition of cyclin-dependent kinase 6 increased de novo lipogenesis in the adipose tissues but not in the liver, which may provide a strategy to concur obesity-induced maladies.
- Alexander J. Hu
- , Wei Li
- & Miaofen G. Hu
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Article
| Open AccessArtesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis
Obesity is a global health challenge with an ongoing need for new medical treatments. Here, the authors show that artesunate, an FDA-approved treatment for severe malaria, can be repurposed for the treatment of obesity via GDF15/GFRAL signaling axis without overt side effects in mice and non-human primates.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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Article
| Open AccessReaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.
- Stanley C. Xie
- , Yinuo Wang
- & Leann Tilley
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Article
| Open AccessElucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins
Mycoplanecins show promising activity against tuberculosis. Here, the authors identify and study mycoplanecins’ biosynthesis, antibacterial effects, and binding mechanism to DnaN, suggesting potential for fighting multidrug-resistant tuberculosis.
- Chengzhang Fu
- , Yunkun Liu
- & Rolf Müller
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Article
| Open AccessDiscovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis
Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), can progress to liver fibrosis. Here, the authors develop a peripheral 5HT2A antagonist for the treatment of MASLD and MASH.
- Haushabhau S. Pagire
- , Suvarna H. Pagire
- & Jin Hee Ahn
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Article
| Open AccessHigh-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
Using an unbiased phenotypic cell-based high-throughput screen, the authors identify and characterize a small molecule, BCH-HSP-C01, that restores aberrant protein trafficking in neuronal models of adapter protein complex 4 deficiency.
- Afshin Saffari
- , Barbara Brechmann
- & Mustafa Sahin
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Article
| Open AccessSelective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines
Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.
- Gisele Nishiguchi
- , Lauren G. Mascibroda
- & Zoran Rankovic
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Article
| Open AccessDesign-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.
- Arun Chandramohan
- , Hubert Josien
- & Anthony W. Partridge
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Article
| Open AccessLigand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.
- Ralph Gradisch
- , Katharina Schlögl
- & Thomas Stockner
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Article
| Open AccessInhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
A pro-tumorigenic role of iRhom1 has been described in several cancer types. Here the authors show that iRhom1 regulates sensitivity to chemotherapy and immune response, as well they report that CD44 targeting nanoparticle-mediated co-delivery of iRhom1 pre-siRNA promotes anti-tumor immune responses in preclinical cancer models.
- Zhangyi Luo
- , Yixian Huang
- & Song Li
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Article
| Open AccessMolecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor
Histamine receptor H1R has been extensively targeted in the development of antihistamines. Here, Wang et al. determine structures of H1R alone and bound to different antihistamines, providing insights into the structure-based design of next-generation drugs.
- Dandan Wang
- , Qiong Guo
- & Yuyong Tao
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Article
| Open AccessA nanoemulsion targeting adipose hypertrophy and hyperplasia shows anti-obesity efficiency in female mice
Adipose tissue enlargement involves adipose hyperplasia and hypertrophy, which correlate with excessive ROS and hyperactivated XBP1. Here, the authors introduce KT-NE, a nanoemulsion combining KIRA6 (an XBP1 inhibitor) and α-Tocopherol, easing ER and oxidative stress in (pre)adipocytes and showing anti-obesity effectiveness.
- Yichao Lu
- , Zhenyu Luo
- & Lihua Luo
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Article
| Open AccessAvapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.
- A. Teuber
- , T. Schulz
- & D. Rauh
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Article
| Open AccessMultiplexed multicolor antiviral assay amenable for high-throughput research
Antiviral approaches against entire genera or families of viruses need to be constantly developed and innovated. Focusing on several distantly-related orthoflaviviruses, the authors develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once.
- Li-Hsin Li
- , Winston Chiu
- & Kai Dallmeier
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Article
| Open AccessMolecular basis of human trace amine-associated receptor 1 activation
hTA1 is a drug target for several neuropsychiatric disorders. Using cryo-EM and pharmacological assays, the authors illuminate hTA1’s similarity to neurotransmitter receptors and discover that the antipsychotic asenapine potently activates the receptor.
- Gregory Zilberg
- , Alexandra K. Parpounas
- & Daniel Wacker
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Article
| Open AccessStructure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity
Wang et al. report on an inhibitor of the lysine methyltransferase KMT9 with cellular activity. The inhibitor blocks proliferation of androgen-resistant prostate cancer cells, opening therapeutics avenues to treat this type of cancer.
- Sheng Wang
- , Sebastian O. Klein
- & Roland Schüle
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Article
| Open AccessIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potential
Serotonin 5-HT2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.
- Jason Wallach
- , Andrew B. Cao
- & John D. McCorvy
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Article
| Open AccessMapping combinatorial drug effects to DNA damage response kinase inhibitors
DNA damage is a key component of many cancer therapies. Here, the authors utilised a dose-response combination screen of ATR, ATM and DNA-PK inhibitors, and identified combination treatments that achieves high combinatorial efficacy and synergy.
- Hanrui Zhang
- , Julian Kreis
- & Yuanfang Guan
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Article
| Open AccessStructures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors
The proteasome of Plasmodium falciparum (Pf20S) is a promising multi-stage drug target. Using CryoEM Hsu et al. report the structures of parasite and human proteasome in complex with the recently developed inhibitor TDI-8304 to gain insights into its species selectivity.
- Hao-Chi Hsu
- , Daqiang Li
- & Gang Lin
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Article
| Open AccessAnti-VEGFR2 F(ab′)2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy
Poor renal distribution of antibody-based drugs limits the treatment efficiency for diabetic nephropathy and causes side effects. Here, the authors prepare an antibody fragment drug conjugate, antiVEGFR2 F(ab′)2-SS31, improving renal distribution and meriting drug validation in diabetic nephropathy therapy.
- Di Liu
- , Yanling Song
- & Yongzhong Du
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Article
| Open AccessLate-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation
PROTACs are uniquely powerful therapeutic agents, but their synthetic tractability significantly limit drug discovery programs. Here, the authors developed a single step synthesis of PROTAC conjugates via late stage ruthenium-catalysed C–H amidation.
- Daniele Antermite
- , Stig D. Friis
- & Magnus J. Johansson
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Article
| Open AccessComplexEye: a multi-lens array microscope for high-throughput embedded immune cell migration analysis
Video microscopy is key in studying cell migration, but accomplishing this in a high-throughput manner is still challenging. Here, the authors present an array microscope that can track the movements of thousands of individual cells simultaneously, and that can be used for drug screening studies.
- Zülal Cibir
- , Jacqueline Hassel
- & Matthias Gunzer
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Article
| Open AccessHigh-throughput target trial emulation for Alzheimer’s disease drug repurposing with real-world data
Target trial emulation (TTE) simulates randomized controlled trials using real world data (RWD). Here, authors show the effectiveness of different TTE strategies to identify drug candidates that could be potentially repurposed to Alzheimer’s disease using two large scale RWD warehouses.
- Chengxi Zang
- , Hao Zhang
- & Fei Wang
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Article
| Open AccessHarnessing PROTAC technology to combat stress hormone receptor activation
Stress-hormone receptors are important therapeutic targets for many diseases but the currently clinically approved inhibitor lacks specificity. Here the authors present a stress hormone receptor depletion tool that differs in its mode of action making it specific in counteracting the effects of stress.
- Mahshid Gazorpak
- , Karina M. Hugentobler
- & Katharina Gapp
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Article
| Open AccessA naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging
Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.
- Carolin Thomas
- , Reto Erni
- & Michael Ristow
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Article
| Open AccessSystemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function
A systemically administered peptide (CARSKNKDC) that homes to injured tissues, has inherent ability to promote wound healing. Here, the authors show that this peptide binds to syndecan-4 and activates ARF6 to trigger re-epithelialisation and the naturally occurring wound repair pathway.
- Horacio Maldonado
- , Bryan D. Savage
- & Tero A. H. Järvinen
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Article
| Open AccessDesign and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor
Despite advances in GPCR structures and peptide design, creating high-affinity ligands remains a challenge. Here the authors develop a computational method, successfully identifying peptide-based molecules for KOR: their platform shows promise for streamlined GPCR ligand discovery.
- Edin Muratspahić
- , Kristine Deibler
- & Christian W. Gruber
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Article
| Open AccessDocking for EP4R antagonists active against inflammatory pain
Non-addictive treatments for pain are much needed. Here, the authors identify in vivo active leads for inflammatory pain using large library docking against the EP4 prostaglandin receptor.
- Stefan Gahbauer
- , Chelsea DeLeon
- & Brian K. Shoichet
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Article
| Open AccessA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection
The authors use lipid nanoparticles (LNPs) that predominantly accumulate in the lung to deliver mRNA encoding for the broadly neutralizing antibody 8-9D, and achieve superior inhibition of SARS-CoV-2 infection in mice compared to control LNPs.
- Wanbo Tai
- , Kai Yang
- & Gong Cheng
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Article
| Open AccessA monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence
Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.
- Ming Jiang
- , Mirjam C. W. Huizenga
- & Mario van der Stelt
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Article
| Open AccessInvestigation of monoclonal antibody CSX-1004 for fentanyl overdose
Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.
- Paul T. Bremer
- , Emily L. Burke
- & Rajeev I. Desai
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Article
| Open AccessA multi-reservoir extruder for time-resolved serial protein crystallography and compound screening at X-ray free-electron lasers
Protein serial crystallography at X-ray free-electron lasers (XFELs) is a powerful technique for structure determination. Here, authors present a device for sample delivery designed to abate challenges to non-specialists allowing for compound screening.
- Maximilian Wranik
- , Michal W. Kepa
- & Jörg Standfuss
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Article
| Open AccessCurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves
Dose-response curves are ubiquitous in pharmacology and biology, yet potency and effect size are often estimated even when there is no response. Here, authors present a statistical framework to assess curve significance and demonstrate how this aids drug mode of action analysis in large public datasets.
- Florian P. Bayer
- , Manuel Gander
- & Matthew The
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Matters Arising
| Open AccessHow carvedilol does not activate β2-adrenoceptors
- Robert J. Lefkowitz
- , Howard A. Rockman
- & Milton Packer