Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach
Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approach...
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Frontiers in Pharmacology
2022
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| Online Access: | https://doi.org/1https://doi.org/10.3389/fphar.2017.006810.3389/fphar.2017.00681 http://hdl.handle.net/11408/4904 |
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| author | Mugumbate, Grace Mendes, Vitor Blaszczyk, Michal Sabbah, Mohamad Papadatos, George Lelievre, Joel Ballell, Lluis Barros, David Abell, Chris Blundell, Tom L. Overington, John P. |
| author_facet | Mugumbate, Grace Mendes, Vitor Blaszczyk, Michal Sabbah, Mohamad Papadatos, George Lelievre, Joel Ballell, Lluis Barros, David Abell, Chris Blundell, Tom L. Overington, John P. |
| author_sort | Mugumbate, Grace |
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| description | Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC50 below 50 μM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect. |
| format | Article |
| id | ir-11408-4904 |
| institution | My University |
| language | English |
| publishDate | 2022 |
| publisher | Frontiers in Pharmacology |
| record_format | dspace |
| spelling | ir-11408-49042022-06-28T09:50:20Z Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach Mugumbate, Grace Mendes, Vitor Blaszczyk, Michal Sabbah, Mohamad Papadatos, George Lelievre, Joel Ballell, Lluis Barros, David Abell, Chris Blundell, Tom L. Overington, John P. Mycobacterium tuberculosis, Phenotypic hits, Target identification, Drug resistance, EthR, InhA Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC50 below 50 μM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect. 2022-06-28T09:50:20Z 2022-06-28T09:50:20Z 2017 Article Mugumbate G, Mendes V, Blaszczyk M, Sabbah M, Papadatos G, Lelievre J, Ballell L, Barros D, Abell C, Blundell TL and Overington JP (2017) Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach. Front. Pharmacol. 8:681. doi: 10.3389/fphar.2017.00681 1663-9812 https://doi.org/1https://doi.org/10.3389/fphar.2017.006810.3389/fphar.2017.00681 http://hdl.handle.net/11408/4904 en open Frontiers in Pharmacology |
| spellingShingle | Mycobacterium tuberculosis, Phenotypic hits, Target identification, Drug resistance, EthR, InhA Mugumbate, Grace Mendes, Vitor Blaszczyk, Michal Sabbah, Mohamad Papadatos, George Lelievre, Joel Ballell, Lluis Barros, David Abell, Chris Blundell, Tom L. Overington, John P. Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach |
| title | Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach |
| title_full | Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach |
| title_fullStr | Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach |
| title_full_unstemmed | Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach |
| title_short | Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach |
| title_sort | target identification of mycobacterium tuberculosis phenotypic hits using a concerted chemogenomic, biophysical, and structural approach |
| topic | Mycobacterium tuberculosis, Phenotypic hits, Target identification, Drug resistance, EthR, InhA |
| url | https://doi.org/1https://doi.org/10.3389/fphar.2017.006810.3389/fphar.2017.00681 http://hdl.handle.net/11408/4904 |
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