Computational study on the selective inhibition mechanism of MS402 to the first and second bromodomains of BRD4.

As a representative member of the bromodomain and extraterminal domain (BET) family, BRD4 is considered as a potential therapeutic target for cancer treatment. However, due to the highly conservation of its two homologous bromodomains (BD1/BD2), selective inhibition of each bromodomain remains a challenge. MS402 is a domain-selective inhibitor of BRD4-BD1 over BRD4-BD2 reported recently. Understanding the detailed molecular mechanism of this selectivity would be very useful for the further design and discovery of more potent selective inhibitors targeting BRD4-BD1. Molecular dynamics simulation, adaptive biasing force (ABF) and multiple-walker adaptive biasing force (MW-ABF) simulations were performed to study the inhibition and domain-selective mechanism of MS402 towards BRD4-BD1 over BRD4-BD2 here. Molecular mechanics/generalized born surface area (MM/GBSA) calculation results demonstrate that BRD4-BD1 binds to MS402 with lower binding free energy than BRD4-BD2. Residues Gln85, Pro86, Asn140 and Ile146 are crucial for MS402's selectively binding to BRD4-BD1. ABF and MW-ABF calculations reveal that MS402 needs to overcome more energy barrier to dissociate from BD1 pocket than from BD2 pocket. The unbinding pathways of MS402 from BD1 and BD2 pockets are also different. We expect that these findings will be helpful for novel inhibitor design and rational structural modification of existing inhibitors to increase their BD1-selectivity. This article is protected by copyright. All rights reserved.