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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
- Source :
- Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017), Scientific Reports
- Publication Year :
- 2017
- Publisher :
- Nature Portfolio, 2017.
-
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.
- Subjects :
- 0301 basic medicine
Quantitative structure–activity relationship
Science
Molecular Conformation
Quantitative Structure-Activity Relationship
Plasma protein binding
RVX 208
Molecular Dynamics Simulation
Protein Serine-Threonine Kinases
Bioinformatics
Article
03 medical and health sciences
chemistry.chemical_compound
Humans
Protein Interaction Domains and Motifs
Binding site
Transcription factor
Quinazolinones
Binding Sites
Multidisciplinary
Molecular Structure
Rational design
Nuclear Proteins
Hydrogen Bonding
Bromodomain
Microsecond
030104 developmental biology
chemistry
Biophysics
Thermodynamics
Medicine
Protein Binding
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....9364eafde4e6decf12817470408222fc