ArticleACS chemical biology2014
A structural and energetic model for the slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA.
Article in ACS chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed.
- 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
- Is Mycobacterial InhA a Suitable Target for Rational Drug Design?ChemMedChem · 2025Review
- Membrane-assisted tariquidar access and binding mechanisms of human ATP-binding cassette transporter P-glycoprotein.Frontiers in molecular biosciences · 2024Article
- Evaluating the Impact of the Tyr158 pBiochemistry · 2023Article
- Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections.International journal of molecular sciences · 2022Article
- 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
- Enhanced-Sampling Simulations for the Estimation of Ligand Binding Kinetics: Current Status and Perspective.Frontiers in molecular biosciences · 2022Review
- Bacterial Enoyl-Reductases: The Ever-Growing List of Fabs, Their Mechanisms and Inhibition.Frontiers in microbiology · 2022Review
- Free Energy Landscapes from SARS-CoV-2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket.Journal of the American Chemical Society · 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
- Protein storytelling through physics.Science (New York, N.Y.) · 2020Review
- Accelerated trypsin autolysis by affinity polymer templates.RSC advances · 2020Article
- Quantifying the Interactions between Biomolecules: Guidelines for Assay Design and Data Analysis.ACS infectious diseases · 2019Article
- Structure-kinetic relationships that control the residence time of drug-target complexes: insights from molecular structure and dynamics.Current opinion in chemical biology · 2018Review
- Drug-Target Kinetics in Drug Discovery.ACS chemical neuroscience · 2018Article
- Examining the role of protein structural dynamics in drug resistance inChemical science · 2017Article
- Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA.Tuberculosis (Edinburgh, Scotland) · 2017Article
- Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening.Nature communications · 2017Article
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9 authors.
Funding
Abstract
Slow-onset enzyme inhibitors are of great interest for drug discovery programs since the slow dissociation of the inhibitor from the drug-target complex results in sustained target occupancy leading to improved pharmacodynamics. However, the structural basis for slow-onset inhibition is often not fully understood, hindering the development of structure-kinetic relationships and the rational optimization of drug-target residence time. Previously we demonstrated that slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA correlated with motions of a substrate-binding loop (SBL) near the active site. In the present work, X-ray crystallography and molecular dynamics simulations have been used to map the structural and energetic changes of the SBL that occur upon enzyme inhibition. Helix-6 within the SBL adopts an open conformation when the inhibitor structure or binding kinetics is substrate-like. In contrast, slow-onset inhibition results in large-scale local refolding in which helix-6 adopts a closed conformation not normally populated during substrate turnover. The open and closed conformations of helix-6 are hypothesized to represent the EI and EI* states on the two-step induced-fit reaction coordinate for enzyme inhibition. These two states were used as the end points for nudged elastic band molecular dynamics simulations resulting in two-dimensional potential energy profiles that reveal the barrier between EI and EI*, thus rationalizing the binding kinetics observed with different inhibitors. Our findings indicate that the structural basis for slow-onset kinetics can be understood once the structures of both EI and EI* have been identified, thus providing a starting point for the rational control of enzyme-inhibitor binding kinetics.
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