ArticleJournal of the American Chemical Society2017
Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 56 citations in OpenAlex.
- Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.bioRxiv : the preprint server for biology · 2026Article
- Altered residence time as a cause of drug resistance.Current opinion in structural biology · 2026Review
- Only time will tell: Modelling the kinetics of covalent inhibitors.British journal of pharmacology · 2026Review
- Consequences of Peptide Macrocyclization Revealed by Virus-Inspired β-Hairpin Mimetics.ACS chemical biology · 2026Article
- Targeting InhA for Tuberculosis Therapy: A Review of Recent Advances in Enzyme Inhibition and Drug Development.Current drug targets · 2026Review
- Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects.Journal of the American Chemical Society · 2025Article
- Is Mycobacterial InhA a Suitable Target for Rational Drug Design?ChemMedChem · 2025Review
- ModBind, a Rapid Simulation-Based Predictor of Ligand Binding and Off-Rates.Journal of chemical information and modeling · 2025Article
- Catalase-peroxidase (KatG): a potential frontier in tuberculosis drug development.Critical reviews in biochemistry and molecular biology · 2024Review
- Article
- Evaluating the Impact of the Tyr158 pBiochemistry · 2023Article
- The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development.Molecular biomedicine · 2022Review
- Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors.Journal of medicinal chemistry · 2022Article
- Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA.International journal of molecular sciences · 2022Article
- Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- A Long Residence Time Enoyl-Reductase Inhibitor Explores an Extended Binding Region with Isoenzyme-Dependent Tautomer Adaptation and Differential Substrate-Binding Loop Closure.ACS infectious diseases · 2021Article
- Exploring the chemical space of 1,2,3-triazolyl triclosan analogs for discovery of new antileishmanial chemotherapeutic agents.RSC medicinal chemistry · 2021Article
- A structure-kinetic relationship study using matched molecular pair analysis.RSC medicinal chemistry · 2020Article
- On Calculating Free Energy Differences Using Ensembles of Transition Paths.Frontiers in molecular biosciences · 2020Article
- Binding kinetics of ligands acting at GPCRs.Molecular and cellular endocrinology · 2019Review
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Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
Abstract
A critical goal of lead compound selection and optimization is to maximize target engagement while minimizing off-target binding. Since target engagement is a function of both the thermodynamics and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, we predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-containing diphenyl ether with an increased residence time on InhA due to transition-state destabilization rather than ground-state stabilization. In the present work, we evaluate the inhibition of InhA by 14 triazole-based diphenyl ethers and use a combination of enzyme kinetics and X-ray crystallography to generate a structure-kinetic relationship for time-dependent binding. We show that the triazole motif slows the rate of formation for the final drug-target complex by up to 3 orders of magnitude. In addition, we identify a novel inhibitor with a residence time on InhA of 220 min, which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.
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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.