Dec 4 2017
Selective inhibition mechanism of RVX-208 to the second bromodomain of bromo and extraterminal proteins: insight from microsecond molecular dynamics simulations.
Dr Elaine Lai Han Leung et al reported the selective mechanism of RVX-208 inhibiting the second bromodomain of bromo and extraterminal proteins and proposed a new corresponding drug design strategy.
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. Although it exhibits the promising antitumor activity against various cancers, 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, recently, Chair Prof. Liu Liang, Prof. Yao Xiao-Jun, Dr. Leung Lai Han and their colleagues from the State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology, MUST), carried out microsecond molecular dynamics simulations for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with/without RVX-208 using the largest high-performance computing center station in Macau. Binding free energy calculations show that there exists strongest interaction between RVX-208 and BRD2-BD2 in three systems. Leu383 and Asn429 are two most important residues of BRD2-BD2 for binding to RVX-208. RVX-208 can shorten the communication path of ZA and BC loops in BRD2-BD2 pocket, making pocket more suitable to accommodate RVX-208. More importantly, the different behaviors of His433 (Asp160 in BRD2-BD1) and Val435 (Ile162 in BRD2-BD1) in BRD2-BD2 are the crucial factors responsible for selective binding of RVX-208 to BRD2-BD2. The proposed selective mechanism and strategy in this study can be helpful for rational design of novel and potential selective inhibitors of the second bromodomain of BET family proteins. This paper was accepted by the journal scientific report of the “Nature Publishing Group” on July 14, 2017. The newly released Impact Factor for scientific report is 4.2 (Thomson Reuters, 2017).