ArticleNature chemical biology2015
Translating slow-binding inhibition kinetics into cellular and in vivo effects.
Article in Nature chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
72 citing papers in PubMed.
- Development of a PK/PD-Efficacy Modeling Framework for Covalent Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Ehrlich occupancy time: beyond [Formula: see text] to a complete residence time framework.Journal of pharmacokinetics and pharmacodynamics · 2026Article
- Decoding Enzyme-Inhibitor Kinetic Mechanisms by Isothermal Titration Calorimetry: The Case of SARS-CoV-2 3CLAnalytical chemistry · 2026Article
- Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.bioRxiv : the preprint server for biology · 2026Article
- PBPK modeling predicts rilzabrutinib dose adjustments using BTK occupancy for CYP3A4 interactions and hepatic impairment.Scientific reports · 2026Article
- Selectivity of the Time-DependentACS chemical biology · 2025Article
- Identifying Modulators of the Post-Antibiotic Effect.ACS infectious diseases · 2025Article
- Advancing Covalent Ligand and Drug Discovery beyond Cysteine.Chemical reviews · 2025Review
- Time-Dependent Inhibition of Leucyl-tRNA-Synthetase (LeuRS): Insight into Target Vulnerability.ACS infectious diseases · 2025Article
- Rapid Determination of Kinetic Constants for Slow-Binding Inhibitors and Inactivators of Human Histone Deacetylase 8.International journal of molecular sciences · 2024Article
- Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton's Tyrosine Kinase.ACS pharmacology & translational science · 2023Article
- Dissociation kinetics of small-molecule inhibitors in Escherichia coli is coupled to physiological state of cells.Communications biology · 2023Article
- Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity.Journal of medicinal chemistry · 2022Article
- Phosphorus containing analogues of SAHA as inhibitors of HDACs.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.Journal of medicinal chemistry · 2022Article
- Simulation of ligand dissociation kinetics from the protein kinase PYK2.Journal of computational chemistry · 2022Article
- Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors.Journal of medicinal chemistry · 2022Article
- Structure-Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds.ACS infectious diseases · 2022Article
- Synthetic oxepanoprolinamide iboxamycin is active againstJAC-antimicrobial resistance · 2022Article
- Quantitative Structure-Activity Relationship (QSAR) Study Predicts Small-Molecule Binding to RNA Structure.Journal of medicinal chemistry · 2022Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors.
Funding
Abstract
Many drug candidates fail in clinical trials owing to a lack of efficacy from limited target engagement or an insufficient therapeutic index. Minimizing off-target effects while retaining the desired pharmacodynamic (PD) response can be achieved by reduced exposure for drugs that display kinetic selectivity in which the drug-target complex has a longer half-life than off-target-drug complexes. However, though slow-binding inhibition kinetics are a key feature of many marketed drugs, prospective tools that integrate drug-target residence time into predictions of drug efficacy are lacking, hindering the integration of drug-target kinetics into the drug discovery cascade. Here we describe a mechanistic PD model that includes drug-target kinetic parameters, including the on- and off-rates for the formation and breakdown of the drug-target complex. We demonstrate the utility of this model by using it to predict dose response curves for inhibitors of the LpxC enzyme from Pseudomonas aeruginosa in an animal model of infection.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.