The relationship between target-class and the physicochemical properties of antibacterial drugs
The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower log P and...
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| Language: | English |
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Elsevier
2022
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| Online Access: | https://doi.org/10.1016/j.bmc.2015.04.063 http://hdl.handle.net/11408/4924 |
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| author | Mugumbate, Grace Overington, John P. |
| author_facet | Mugumbate, Grace Overington, John P. |
| author_sort | Mugumbate, Grace |
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| description | The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower log P and higher polar surface area (PSA). By analysing the physicochemical properties of about 1700 approved drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins (i.e., composed of a complex of RNA and protein) fall outside the conventional human ‘drug-like’ chemical space; whereas antibacterials that modulate bacterial protein targets, generally comply with the ‘rule-of-five’ guidelines for classical oral human drugs. Our analysis suggests a strong target-class association for antibacterials—either protein-targeted or riboprotein-targeted. There is much discussion in the literature on the failure of screening approaches to deliver novel antibacterial lead series, and linkage of this poor success rate for antibacterials with the chemical space properties of screening collections. Our analysis suggests that consideration of target-class may be an underappreciated factor in antibacterial lead discovery, and that in fact bacterial protein-targets may well have similar binding site characteristics to human protein targets, and questions the assumption that larger, more polar compounds are a key part of successful future antibacterial discovery. |
| format | Article |
| id | ir-11408-4924 |
| institution | My University |
| language | English |
| publishDate | 2022 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | ir-11408-49242022-06-28T12:30:41Z The relationship between target-class and the physicochemical properties of antibacterial drugs Mugumbate, Grace Overington, John P. Antibacterials Physicochemical properties Drug targets Ribosome The discovery of novel mechanism of action (MOA) antibacterials has been associated with the concept that antibacterial drugs occupy a differentiated region of physicochemical space compared to human-targeted drugs. With, in broad terms, antibacterials having higher molecular weight, lower log P and higher polar surface area (PSA). By analysing the physicochemical properties of about 1700 approved drugs listed in the ChEMBL database, we show, that antibacterials for whose targets are riboproteins (i.e., composed of a complex of RNA and protein) fall outside the conventional human ‘drug-like’ chemical space; whereas antibacterials that modulate bacterial protein targets, generally comply with the ‘rule-of-five’ guidelines for classical oral human drugs. Our analysis suggests a strong target-class association for antibacterials—either protein-targeted or riboprotein-targeted. There is much discussion in the literature on the failure of screening approaches to deliver novel antibacterial lead series, and linkage of this poor success rate for antibacterials with the chemical space properties of screening collections. Our analysis suggests that consideration of target-class may be an underappreciated factor in antibacterial lead discovery, and that in fact bacterial protein-targets may well have similar binding site characteristics to human protein targets, and questions the assumption that larger, more polar compounds are a key part of successful future antibacterial discovery. 2022-06-28T12:30:41Z 2022-06-28T12:30:41Z 2015 Article 0968-0896 https://doi.org/10.1016/j.bmc.2015.04.063 http://hdl.handle.net/11408/4924 en Bioorganic and Medicinal Chemistry;Vol. 23 (16); Pages 5218–5224 open Elsevier |
| spellingShingle | Antibacterials Physicochemical properties Drug targets Ribosome Mugumbate, Grace Overington, John P. The relationship between target-class and the physicochemical properties of antibacterial drugs |
| title | The relationship between target-class and the physicochemical properties of antibacterial drugs |
| title_full | The relationship between target-class and the physicochemical properties of antibacterial drugs |
| title_fullStr | The relationship between target-class and the physicochemical properties of antibacterial drugs |
| title_full_unstemmed | The relationship between target-class and the physicochemical properties of antibacterial drugs |
| title_short | The relationship between target-class and the physicochemical properties of antibacterial drugs |
| title_sort | relationship between target-class and the physicochemical properties of antibacterial drugs |
| topic | Antibacterials Physicochemical properties Drug targets Ribosome |
| url | https://doi.org/10.1016/j.bmc.2015.04.063 http://hdl.handle.net/11408/4924 |
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