A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4
Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational method...
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| Format: | Article |
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MDPI AG
2015-08-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/20/8/14915 |
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| author | Suresh Panneerselvam Dhanusha Yesudhas Prasannavenkatesh Durai Muhammad Ayaz Anwar Vijayakumar Gosu Sangdun Choi |
| author_facet | Suresh Panneerselvam Dhanusha Yesudhas Prasannavenkatesh Durai Muhammad Ayaz Anwar Vijayakumar Gosu Sangdun Choi |
| author_sort | Suresh Panneerselvam |
| collection | DOAJ |
| description | Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson–Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs. |
| first_indexed | 2024-12-20T17:12:55Z |
| format | Article |
| id | doaj.art-b9e391497a2d4c59aeee0274556ddde7 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-20T17:12:55Z |
| publishDate | 2015-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b9e391497a2d4c59aeee0274556ddde72022-12-21T19:32:05ZengMDPI AGMolecules1420-30492015-08-01208149151493510.3390/molecules200814915molecules200814915A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4Suresh Panneerselvam0Dhanusha Yesudhas1Prasannavenkatesh Durai2Muhammad Ayaz Anwar3Vijayakumar Gosu4Sangdun Choi5Department of Molecular Science and Technology, Ajou University, Suwon 443-749, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 443-749, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 443-749, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 443-749, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 443-749, KoreaDepartment of Molecular Science and Technology, Ajou University, Suwon 443-749, KoreaCytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson–Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs.http://www.mdpi.com/1420-3049/20/8/14915CYP450drug metabolismdockingmolecular dynamics simulation |
| spellingShingle | Suresh Panneerselvam Dhanusha Yesudhas Prasannavenkatesh Durai Muhammad Ayaz Anwar Vijayakumar Gosu Sangdun Choi A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4 Molecules CYP450 drug metabolism docking molecular dynamics simulation |
| title | A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4 |
| title_full | A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4 |
| title_fullStr | A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4 |
| title_full_unstemmed | A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4 |
| title_short | A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4 |
| title_sort | combined molecular docking dynamics approach to probe the binding mode of cancer drugs with cytochrome p450 3a4 |
| topic | CYP450 drug metabolism docking molecular dynamics simulation |
| url | http://www.mdpi.com/1420-3049/20/8/14915 |
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