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.
Highlights
Bromodomains (BRDs) are protein modulators that recognize acetylated lysine-containing sequences as an “epigenetic reader”
Microsecond molecular dynamics simulations were performed in this study to investigate the binding modes of RVX-208 with bromodomain of BET proteins and to elucidate the selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins
With respect to the starting structure, root-mean-square deviations (RMSDs) of protein CA atoms, heavy atoms of RVX-208, CA atoms of active site in holo and apo systems of BRD2-BD1 and BRD2-BD2 were monitored to assess the overall stability of simulations
Summary
Bromodomains (BRDs) are protein modulators that recognize acetylated lysine-containing sequences as an “epigenetic reader”. Structural analyses show that all four BET proteins and two homologous bromodomains (BD1/2) of each protein are highly conserved[1], and selective inhibition of either BD1 or BD2 can result in distinct transcriptional outcomes[21, 26,27,28]. The domain-specific inhibitors against BETs are highly needed to avoid adverse effects of prolonged pan-BET inhibition. Microsecond molecular dynamics simulations were performed in this study to investigate the binding modes of RVX-208 with bromodomain of BET proteins and to elucidate the selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins
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