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Issue 35, 2018
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Classical molecular dynamics and metadynamics simulations decipher the mechanism of CBP30 selectively inhibiting CBP/p300 bromodomains

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Abstract

The selective modulation of individual bromodomains (BDs) by small molecules represents an important strategy for the treatment of various cancers, considering that the BD-containing proteins share common BD structures and distinct pharmacological functions. Small molecule inhibitors targeting BDs outside of the bromodomain and extraterminal domain (BET, including BRD2–4 and BRDT) family are particularly lacking. CBP30 exhibited excellent selectivity for the transcriptional coactivators CBP (CREB binding protein) and p300 bromodomains, providing a new opportunity for designing selective non-BET inhibitors. Here, we performed classical molecular dynamics (cMD) and metadynamics simulations to reveal the selective mechanism of CBP30 binding with CBP/p300 and BRD4-BD1/BD2 bromodomains. The cMD simulations combined with binding free energy calculations were performed to compare the overall features of CBP30 binding with CBP/p300 and BRD4-BD1/BD2 bromodomains. Arg1173/1137, as the unique residue for CBP/p300, was responsible for the selective binding to CBP30 via cation–π and hydrogen bond interactions. Metadynamics simulation, together with unbinding free energy profiles, suggested that the dissociation pathways of CBP30 from CBP/p300 and BRD4-BD1/BD2 bromodomains were different, with the unbinding of the former being more difficult. These findings will be helpful for novel CBP/p300-inhibitor design and rational structural modification of existing inhibitors to increase their selectivity.

Graphical abstract: Classical molecular dynamics and metadynamics simulations decipher the mechanism of CBP30 selectively inhibiting CBP/p300 bromodomains

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Publication details

The article was received on 28 Jun 2018, accepted on 17 Aug 2018 and first published on 20 Aug 2018


Article type: Paper
DOI: 10.1039/C8OB01526K
Citation: Org. Biomol. Chem., 2018,16, 6521-6530
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    Classical molecular dynamics and metadynamics simulations decipher the mechanism of CBP30 selectively inhibiting CBP/p300 bromodomains

    Q. Wang, X. An, J. Xu, Y. Wang, L. Liu, E. L. Leung and X. Yao, Org. Biomol. Chem., 2018, 16, 6521
    DOI: 10.1039/C8OB01526K

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