Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors
Bromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targ...
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MDPI AG
2021-12-01
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| author | Siao Chen Yi He Yajiao Geng Zhi Wang Lu Han Weiwei Han |
| author_facet | Siao Chen Yi He Yajiao Geng Zhi Wang Lu Han Weiwei Han |
| author_sort | Siao Chen |
| collection | DOAJ |
| description | Bromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targeting androgen-receptor (AR)-driven cancers. In order to explore the effect of inhibitors binding to BRD4 (the most studied member of BET family), four 150 ns molecular dynamic simulations were performed (free BRD4, Cpd4-BRD4, Cpd9-BRD4 and Cpd19-BRD4). Docking studies showed that Cpd9 and Cpd19 were located at the active pocket, as well as Cpd4. Molecular dynamics (MD) simulations indicated that only Cpd19 binding to BRD4 can induce residue Trp81-Ala89 partly become α-helix during MD simulations. MM-GBSA calculations suggested that Cpd19 had the best binding effect with BRD4 followed by Cpd4 and Cpd9. Computational alanine scanning results indicated that mutations in Phe83 made the greatest effects in Cpd9-BRD4 and Cpd19-BRD4 complexes, showing that Phe83 may play crucial roles in Cpd9 and Cpd19 binding to BRD4. Our results can provide some useful clues for further BCPs family search. |
| first_indexed | 2024-03-10T03:30:47Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:30:47Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-5b392baafe534d98bee854b729a182932023-11-23T11:56:58ZengMDPI AGMolecules1420-30492021-12-0127111810.3390/molecules27010118Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent InhibitorsSiao Chen0Yi He1Yajiao Geng2Zhi Wang3Lu Han4Weiwei Han5Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, ChinaKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, ChinaKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, ChinaKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, ChinaKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, ChinaKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, ChinaBromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targeting androgen-receptor (AR)-driven cancers. In order to explore the effect of inhibitors binding to BRD4 (the most studied member of BET family), four 150 ns molecular dynamic simulations were performed (free BRD4, Cpd4-BRD4, Cpd9-BRD4 and Cpd19-BRD4). Docking studies showed that Cpd9 and Cpd19 were located at the active pocket, as well as Cpd4. Molecular dynamics (MD) simulations indicated that only Cpd19 binding to BRD4 can induce residue Trp81-Ala89 partly become α-helix during MD simulations. MM-GBSA calculations suggested that Cpd19 had the best binding effect with BRD4 followed by Cpd4 and Cpd9. Computational alanine scanning results indicated that mutations in Phe83 made the greatest effects in Cpd9-BRD4 and Cpd19-BRD4 complexes, showing that Phe83 may play crucial roles in Cpd9 and Cpd19 binding to BRD4. Our results can provide some useful clues for further BCPs family search.https://www.mdpi.com/1420-3049/27/1/118bromodomain and extra-terminal protein 4 (BRD4)inhibitorsmolecular dynamic simulationsconformational changesMM-GBSA calculations |
| spellingShingle | Siao Chen Yi He Yajiao Geng Zhi Wang Lu Han Weiwei Han Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors Molecules bromodomain and extra-terminal protein 4 (BRD4) inhibitors molecular dynamic simulations conformational changes MM-GBSA calculations |
| title | Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors |
| title_full | Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors |
| title_fullStr | Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors |
| title_full_unstemmed | Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors |
| title_short | Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors |
| title_sort | molecular dynamic simulations of bromodomain and extra terminal protein 4 bonded to potent inhibitors |
| topic | bromodomain and extra-terminal protein 4 (BRD4) inhibitors molecular dynamic simulations conformational changes MM-GBSA calculations |
| url | https://www.mdpi.com/1420-3049/27/1/118 |
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