Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations

Abstract RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the fir...

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Autores principales:	Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Elaine Lai-Han Leung, Liang Liu, Xiaojun Yao
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a143d8ecc28c4c46bb322c86581af140
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spelling	oai:doaj.org-article:a143d8ecc28c4c46bb322c86581af1402021-12-02T16:06:57ZSelective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations10.1038/s41598-017-08909-82045-2322https://doaj.org/article/a143d8ecc28c4c46bb322c86581af1402017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08909-8https://doaj.org/toc/2045-2322Abstract RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the first and second bromodomains (BD1 and BD2), the detailed selectivity mechanism of RVX-208 towards BD2 over BD1 is still unknown. To elucidate selective inhibition mechanism of RVX-208 to BD2, microsecond molecular dynamics simulations were performed in this study for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with and without RVX-208, respectively. Binding free energy calculations show that there exists strongest interaction between RVX-208 and BRD2-BD2. Leu383 and Asn429 are two most important residues of BRD2-BD2 for binding to RVX-208. Structural network analysis reveals that RVX-208 can shorten the communication path of ZA and BC loops in BRD2-BD2 pocket, making pocket more suitable to accommodate RVX-208. Additionally, different behaviors of His433 (Asp160 in BRD2-BD1) and Val435 (Ile162 in BRD2-BD1) in BRD2-BD2 are key factors responsible for selective binding of RVX-208 to BRD2-BD2. The proposed selective inhibition mechanism of RVX-208 to BRD2-BD2 can be helpful for rational design of novel selective inhibitors of the second bromodomain of BET family proteins.Qianqian WangYing LiJiahui XuYuwei WangElaine Lai-Han LeungLiang LiuXiaojun YaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Qianqian Wang Ying Li Jiahui Xu Yuwei Wang Elaine Lai-Han Leung Liang Liu Xiaojun Yao Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
description	Abstract RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the first and second bromodomains (BD1 and BD2), the detailed selectivity mechanism of RVX-208 towards BD2 over BD1 is still unknown. To elucidate selective inhibition mechanism of RVX-208 to BD2, microsecond molecular dynamics simulations were performed in this study for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with and without RVX-208, respectively. Binding free energy calculations show that there exists strongest interaction between RVX-208 and BRD2-BD2. Leu383 and Asn429 are two most important residues of BRD2-BD2 for binding to RVX-208. Structural network analysis reveals that RVX-208 can shorten the communication path of ZA and BC loops in BRD2-BD2 pocket, making pocket more suitable to accommodate RVX-208. Additionally, different behaviors of His433 (Asp160 in BRD2-BD1) and Val435 (Ile162 in BRD2-BD1) in BRD2-BD2 are key factors responsible for selective binding of RVX-208 to BRD2-BD2. The proposed selective inhibition mechanism of RVX-208 to BRD2-BD2 can be helpful for rational design of novel selective inhibitors of the second bromodomain of BET family proteins.
format	article
author	Qianqian Wang Ying Li Jiahui Xu Yuwei Wang Elaine Lai-Han Leung Liang Liu Xiaojun Yao
author_facet	Qianqian Wang Ying Li Jiahui Xu Yuwei Wang Elaine Lai-Han Leung Liang Liu Xiaojun Yao
author_sort	Qianqian Wang
title	Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
title_short	Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
title_full	Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
title_fullStr	Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
title_full_unstemmed	Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
title_sort	selective inhibition mechanism of rvx-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a143d8ecc28c4c46bb322c86581af140
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Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations

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