Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations.
作者： Qianqian Wang , Ying Li , Jiahui Xu , Yuwei Wang , Elaine Lai-Han Leung
DOI: 10.1038/S41598-017-08909-8
关键词:
摘要: RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite its promising antitumor activity, due to conserved folds first bromodomains (BD1 BD2), detailed mechanism towards BD2 over BD1 still unknown. To elucidate selective inhibition BD2, microsecond molecular dynamics simulations were performed this study BRD2-BD1, BRD2-BD2 BRD4-BD1 without RVX-208, respectively. Binding free energy calculations show that there exists strongest interaction between BRD2-BD2. Leu383 Asn429 are two most important residues binding RVX-208. Structural network analysis reveals can shorten communication path ZA BC loops pocket, making pocket more suitable accommodate Additionally, different behaviors His433 (Asp160 BRD2-BD1) Val435 (Ile162 key factors responsible The proposed be helpful rational design novel inhibitors BET proteins.
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