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

Organic & Biomolecular Chemistry
Qianqian WangXiaojun Yao

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/p3...Continue Reading

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Citations

Oct 2, 2019·Physical Chemistry Chemical Physics : PCCP·Shuaizhen TianTong Zhu
Aug 28, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Qianqian WangXiaojun Yao
Nov 4, 2021·Expert Opinion on Drug Discovery·Qianqian ZhangHuanxiang Liu

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Methods Mentioned

BETA
protein folding

Software Mentioned

NAMD2
Prime Preparation
iTOL
R
cMD
AMBER ff14SB
Schrödinger suite
AMBER16
Gaussian09
PLUMED2

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