Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol
Thiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the careful watch of FDA...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/3/315 |
| _version_ | 1797416981450719232 |
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| author | Katarina Kores Janez Konc Urban Bren |
| author_facet | Katarina Kores Janez Konc Urban Bren |
| author_sort | Katarina Kores |
| collection | DOAJ |
| description | Thiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the careful watch of FDA for a long time due to suspicion, that it causes cardiovascular diseases, such as heart failure and stroke. We applied a novel inverse molecular docking protocol to discern the potential protein targets of both drugs. Troglitazone and rosiglitazone were docked into predicted binding sites of >67,000 protein structures from the Protein Data Bank and examined. Several new potential protein targets with successfully docked troglitazone and rosiglitazone were identified. The focus was devoted to human proteins so that existing or new potential side effects could be explained or proposed. Certain targets of troglitazone such as 3-oxo-5-beta-steroid 4-dehydrogenase, neutrophil collagenase, stromelysin-1, and VLCAD were pinpointed, which could explain its hepatoxicity, with additional ones indicating that its application could lead to the treatment/development of cancer. Results for rosiglitazone discerned its interaction with members of the matrix metalloproteinase family, which could lead to cancer and neurodegenerative disorders. The concerning cardiovascular side effects of rosiglitazone could also be explained. We firmly believe that our results deepen the mechanistic understanding of the side effects of both drugs, and potentially with further development and research maybe even help to minimize them. On the other hand, the novel inverse molecular docking protocol on the other hand carries the potential to develop into a standard tool to predict possible cross-interactions of drug candidates potentially leading to adverse side effects. |
| first_indexed | 2024-03-09T06:12:16Z |
| format | Article |
| id | doaj.art-0f06b41587d84cfca18a91bf16166d7f |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T06:12:16Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-0f06b41587d84cfca18a91bf16166d7f2023-12-03T11:57:05ZengMDPI AGPharmaceutics1999-49232021-02-0113331510.3390/pharmaceutics13030315Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking ProtocolKatarina Kores0Janez Konc1Urban Bren2Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty for Chemistry and Chemical Technology, University of Maribor, Smetanova 17, SI-2000 Maribor, SloveniaLaboratory of Physical Chemistry and Chemical Thermodynamics, Faculty for Chemistry and Chemical Technology, University of Maribor, Smetanova 17, SI-2000 Maribor, SloveniaLaboratory of Physical Chemistry and Chemical Thermodynamics, Faculty for Chemistry and Chemical Technology, University of Maribor, Smetanova 17, SI-2000 Maribor, SloveniaThiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the careful watch of FDA for a long time due to suspicion, that it causes cardiovascular diseases, such as heart failure and stroke. We applied a novel inverse molecular docking protocol to discern the potential protein targets of both drugs. Troglitazone and rosiglitazone were docked into predicted binding sites of >67,000 protein structures from the Protein Data Bank and examined. Several new potential protein targets with successfully docked troglitazone and rosiglitazone were identified. The focus was devoted to human proteins so that existing or new potential side effects could be explained or proposed. Certain targets of troglitazone such as 3-oxo-5-beta-steroid 4-dehydrogenase, neutrophil collagenase, stromelysin-1, and VLCAD were pinpointed, which could explain its hepatoxicity, with additional ones indicating that its application could lead to the treatment/development of cancer. Results for rosiglitazone discerned its interaction with members of the matrix metalloproteinase family, which could lead to cancer and neurodegenerative disorders. The concerning cardiovascular side effects of rosiglitazone could also be explained. We firmly believe that our results deepen the mechanistic understanding of the side effects of both drugs, and potentially with further development and research maybe even help to minimize them. On the other hand, the novel inverse molecular docking protocol on the other hand carries the potential to develop into a standard tool to predict possible cross-interactions of drug candidates potentially leading to adverse side effects.https://www.mdpi.com/1999-4923/13/3/315thiazolidinedionesrosiglitazonetroglitazoneinverse molecular dockingside effectsCANDOCK |
| spellingShingle | Katarina Kores Janez Konc Urban Bren Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol Pharmaceutics thiazolidinediones rosiglitazone troglitazone inverse molecular docking side effects CANDOCK |
| title | Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol |
| title_full | Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol |
| title_fullStr | Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol |
| title_full_unstemmed | Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol |
| title_short | Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol |
| title_sort | mechanistic insights into side effects of troglitazone and rosiglitazone using a novel inverse molecular docking protocol |
| topic | thiazolidinediones rosiglitazone troglitazone inverse molecular docking side effects CANDOCK |
| url | https://www.mdpi.com/1999-4923/13/3/315 |
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