Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4
Bromodomain-Containing Protein 4 (BRD4) can play an important role in gene transcriptional regulation of tumor development and survival by participating in histone modification epigenetic mechanism. Although it has been reported that novel allosteric inhibitors such as ZL0590 have a high affinity wi...
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| author | Xiaotang Yang Yilin Gao Fuyan Cao Song Wang |
| author_facet | Xiaotang Yang Yilin Gao Fuyan Cao Song Wang |
| author_sort | Xiaotang Yang |
| collection | DOAJ |
| description | Bromodomain-Containing Protein 4 (BRD4) can play an important role in gene transcriptional regulation of tumor development and survival by participating in histone modification epigenetic mechanism. Although it has been reported that novel allosteric inhibitors such as ZL0590 have a high affinity with target protein BRD4 and good efficacy, their inhibitory mechanism has not been studied further. The aim of this study was to reveal the inhibition mechanism of allosteric inhibitor ZL0590 on Free-BRD4 and BRD4 binding MS436 (orthosteric inhibitor) by molecular dynamics simulation combined with a Markov model. Our results showed that BRD4-ZL0590 led to α-helices formation of 100–105 compared with Free-BRD4; the combination of MS436 caused residues 30–40 and 95–105 to form α-helices, while the combination of allosteric inhibitors untangled the α-helices formed by the MS436. The results of Markov flux analysis showed that the binding process of inhibitors mainly involved changes in the degree of α-helices at ZA loop. The binding of ZL0590 reduced the distance between ZA loop and BC loop, blocked the conformation at the active site, and inhibited the binding of MS436. After the allosteric inhibitor binding, the MS436 that could normally penetrate into the interior of the pocket was floating on the edge of the active pocket and did not continue to penetrate into the active pocket as expected. In summary, we provide a theoretical basis for the inhibition mechanism of ZL0590 against BRD4, which can be used as a reference for improving the development of drug targets for cancer therapy. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:39:18Z |
| publishDate | 2023-06-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-afa248f87ea6491ab9097bf8d9eeff0b2023-11-18T16:44:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-0124131083110.3390/ijms241310831Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4Xiaotang Yang0Yilin Gao1Fuyan Cao2Song Wang3Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, ChinaKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, ChinaKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun 130012, ChinaThe Institute of Theoretical Chemistry, College of Chemistry, Jilin University, 2 Liutiao Road, Changchun 130012, ChinaBromodomain-Containing Protein 4 (BRD4) can play an important role in gene transcriptional regulation of tumor development and survival by participating in histone modification epigenetic mechanism. Although it has been reported that novel allosteric inhibitors such as ZL0590 have a high affinity with target protein BRD4 and good efficacy, their inhibitory mechanism has not been studied further. The aim of this study was to reveal the inhibition mechanism of allosteric inhibitor ZL0590 on Free-BRD4 and BRD4 binding MS436 (orthosteric inhibitor) by molecular dynamics simulation combined with a Markov model. Our results showed that BRD4-ZL0590 led to α-helices formation of 100–105 compared with Free-BRD4; the combination of MS436 caused residues 30–40 and 95–105 to form α-helices, while the combination of allosteric inhibitors untangled the α-helices formed by the MS436. The results of Markov flux analysis showed that the binding process of inhibitors mainly involved changes in the degree of α-helices at ZA loop. The binding of ZL0590 reduced the distance between ZA loop and BC loop, blocked the conformation at the active site, and inhibited the binding of MS436. After the allosteric inhibitor binding, the MS436 that could normally penetrate into the interior of the pocket was floating on the edge of the active pocket and did not continue to penetrate into the active pocket as expected. In summary, we provide a theoretical basis for the inhibition mechanism of ZL0590 against BRD4, which can be used as a reference for improving the development of drug targets for cancer therapy.https://www.mdpi.com/1422-0067/24/13/10831Bromodomain-Containing Protein 4 (BRD4)allosteric regulationmolecular dynamics simulationsMarkov modelconformational changes |
| spellingShingle | Xiaotang Yang Yilin Gao Fuyan Cao Song Wang Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4 International Journal of Molecular Sciences Bromodomain-Containing Protein 4 (BRD4) allosteric regulation molecular dynamics simulations Markov model conformational changes |
| title | Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4 |
| title_full | Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4 |
| title_fullStr | Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4 |
| title_full_unstemmed | Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4 |
| title_short | Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4 |
| title_sort | molecular dynamics simulations combined with markov model to explore the effect of allosteric inhibitor binding on bromodomain containing protein 4 |
| topic | Bromodomain-Containing Protein 4 (BRD4) allosteric regulation molecular dynamics simulations Markov model conformational changes |
| url | https://www.mdpi.com/1422-0067/24/13/10831 |
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