An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway
Enzymes belonging to the shikimate pathway have long been considered promising targets for antibacterial drugs because they have no counterpart in mammals and are essential for bacterial growth and virulence. However, despite decades of research, there are currently no clinically relevant antibacter...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/5/675 |
| _version_ | 1797502076679356416 |
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| author | Rok Frlan |
| author_facet | Rok Frlan |
| author_sort | Rok Frlan |
| collection | DOAJ |
| description | Enzymes belonging to the shikimate pathway have long been considered promising targets for antibacterial drugs because they have no counterpart in mammals and are essential for bacterial growth and virulence. However, despite decades of research, there are currently no clinically relevant antibacterial drugs targeting any of these enzymes, and there are legitimate concerns about whether they are sufficiently druggable, i.e., whether they can be adequately modulated by small and potent drug-like molecules. In the present work, in silico analyses combining evolutionary conservation and druggability are performed to determine whether these enzymes are candidates for broad-spectrum antibacterial therapy. The results presented here indicate that the substrate-binding sites of most enzymes in this pathway are suitable drug targets because of their reasonable conservation and druggability scores. An exception was the substrate-binding site of 3-deoxy-<i>D</i>-arabino-heptulosonate-7-phosphate synthase, which was found to be undruggable because of its high content of charged residues and extremely high overall polarity. Although the presented study was designed from the perspective of broad-spectrum antibacterial drug development, this workflow can be readily applied to any antimicrobial target analysis, whether narrow- or broad-spectrum. Moreover, this research also contributes to a deeper understanding of these enzymes and provides valuable insights into their properties. |
| first_indexed | 2024-03-10T03:27:42Z |
| format | Article |
| id | doaj.art-d11aa5b8f5ba41de9066dceda3ae3585 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T03:27:42Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-d11aa5b8f5ba41de9066dceda3ae35852023-11-23T09:49:30ZengMDPI AGAntibiotics2079-63822022-05-0111567510.3390/antibiotics11050675An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate PathwayRok Frlan0The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, SloveniaEnzymes belonging to the shikimate pathway have long been considered promising targets for antibacterial drugs because they have no counterpart in mammals and are essential for bacterial growth and virulence. However, despite decades of research, there are currently no clinically relevant antibacterial drugs targeting any of these enzymes, and there are legitimate concerns about whether they are sufficiently druggable, i.e., whether they can be adequately modulated by small and potent drug-like molecules. In the present work, in silico analyses combining evolutionary conservation and druggability are performed to determine whether these enzymes are candidates for broad-spectrum antibacterial therapy. The results presented here indicate that the substrate-binding sites of most enzymes in this pathway are suitable drug targets because of their reasonable conservation and druggability scores. An exception was the substrate-binding site of 3-deoxy-<i>D</i>-arabino-heptulosonate-7-phosphate synthase, which was found to be undruggable because of its high content of charged residues and extremely high overall polarity. Although the presented study was designed from the perspective of broad-spectrum antibacterial drug development, this workflow can be readily applied to any antimicrobial target analysis, whether narrow- or broad-spectrum. Moreover, this research also contributes to a deeper understanding of these enzymes and provides valuable insights into their properties.https://www.mdpi.com/2079-6382/11/5/675shikimate pathwaydruggabilityligandabilityantibacterialinhibitorsbroad-spectrum |
| spellingShingle | Rok Frlan An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway Antibiotics shikimate pathway druggability ligandability antibacterial inhibitors broad-spectrum |
| title | An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway |
| title_full | An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway |
| title_fullStr | An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway |
| title_full_unstemmed | An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway |
| title_short | An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway |
| title_sort | evolutionary conservation and druggability analysis of enzymes belonging to the bacterial shikimate pathway |
| topic | shikimate pathway druggability ligandability antibacterial inhibitors broad-spectrum |
| url | https://www.mdpi.com/2079-6382/11/5/675 |
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