Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode
| Autor: | M. Daben J. Libardo, Monica Kasbekar, Helena I. Boshoff, Chris Abell, Craig J. Thomas, Clifton E. Barry, Paul Brear, Gerhard Fischer, Anthony G. Coyne, Andrew J. Whitehouse |
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| Přispěvatelé: | Libardo, M Daben J [0000-0003-0037-7812], Boshoff, Helena IM [0000-0002-4333-206X], Coyne, Anthony G [0000-0003-0205-5630], Abell, Chris [0000-0001-9174-1987], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Protein Conformation Allosteric regulation Antitubercular Agents 01 natural sciences Fumarate Hydratase Mycobacterium tuberculosis 03 medical and health sciences Structure-Activity Relationship Drug Delivery Systems Drug Discovery Structure–activity relationship Humans Binding site 030304 developmental biology 0303 health sciences Binding Sites biology Molecular Structure Chemistry Active site biology.organism_classification In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Structural biology Biochemistry Fumarase biology.protein Molecular Medicine |
| DOI: | 10.17863/cam.43912 |
| Popis: | With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations. |
| Databáze: | OpenAIRE |
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