Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors
| Autor: | Sandra Eltschkner, Weixuan Yu, Jonathan Merino, Caroline Kisker, James J. Truglio, Eleanor K. H. Allen, Ben Moree, Neil Thivalapill, Shabnam Davoodi, Lauren A. Spagnuolo, Peter J. Tonge, Joshua Salafsky, Richard A. Slayden, Fereidoon Daryaee, Annica Pschibul, Susan E. Knudson |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Time Factors Stereochemistry Kinetics Triazole Crystallography X-Ray Biochemistry Article Catalysis Reaction coordinate 03 medical and health sciences chemistry.chemical_compound Colloid and Surface Chemistry Humans Inhibins Enzyme kinetics Molecular Structure Chemistry INHA Diphenyl ether General Chemistry Triazoles Combinatorial chemistry Transition state 030104 developmental biology Thermodynamics Lead compound |
| Zdroj: | Journal of the American Chemical Society. 139:3417-3429 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.6b11148 |
| Popis: | A critical goal of lead compound selection and optimization is to maximize target engagement whilst 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 have evaluated the inhibition of InhA by 14 triazole-based diphenyl ethers and used a combination of enzyme kinetics and X-ray crystallography to generate a structure-kinetic relationship (SKR) for time-dependent binding. We show that the triazole motif slows the rate of formation for the final drug-target complex by up to three 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. |
| Databáze: | OpenAIRE |
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