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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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Detalles Bibliográficos
Autores principales: Yang, Xiaotang, Gao, Yilin, Cao, Fuyan, Wang, Song
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10342045/
https://www.ncbi.nlm.nih.gov/pubmed/37446009
http://dx.doi.org/10.3390/ijms241310831
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author Yang, Xiaotang
Gao, Yilin
Cao, Fuyan
Wang, Song
author_facet Yang, Xiaotang
Gao, Yilin
Cao, Fuyan
Wang, Song
author_sort Yang, Xiaotang
collection PubMed
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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spelling pubmed-103420452023-07-14 Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4 Yang, Xiaotang Gao, Yilin Cao, Fuyan Wang, Song Int J Mol Sci Article 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. MDPI 2023-06-29 /pmc/articles/PMC10342045/ /pubmed/37446009 http://dx.doi.org/10.3390/ijms241310831 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Xiaotang
Gao, Yilin
Cao, Fuyan
Wang, Song
Molecular Dynamics Simulations Combined with Markov Model to Explore the Effect of Allosteric Inhibitor Binding on Bromodomain-Containing Protein 4
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10342045/
https://www.ncbi.nlm.nih.gov/pubmed/37446009
http://dx.doi.org/10.3390/ijms241310831
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