溴尿嘧啶
化学
BRD4
选择性
分子动力学
表观遗传学
生物物理学
立体化学
生物化学
计算化学
生物
基因
催化作用
作者
Mingsong Shi,Xueting Zheng,Yan Zhou,Yuan Yin,Lu Zhou,Zhiyan Zou,Yan Hu,Yuanyuan Liang,Tingting Chen,Yuhan Yang,Jing Meng,Dan Lei,Pei Yang,Xiaoan Li
出处
期刊:ACS omega
[American Chemical Society]
日期:2023-09-06
卷期号:8 (37): 33658-33674
标识
DOI:10.1021/acsomega.3c03935
摘要
Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases; therefore, they are interesting targets. BET has two bromodomains: bromodomain 1 (BD1) and BD2. Selective targeting of BD1 or BD2 may produce different activities and greater effects than pan-BD inhibitors. However, the selective mechanism of the specific core must be studied at the atomic level. This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). Molecular dynamics simulations and calculations of binding free energies were used to systematically study the selectivity of BD2 inhibition by the pyrrolopyridone analogues. Overall, the pyrrolopyridone analogue inhibitors targeting BD2 interacted mainly with the following amino acid pairs between bromodomain-containing protein 4 (BRD4)-BD1 and BRD4-BD2 complexes: I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432. The pyrrolopyridone analogues targeting BRD4-BD2 were divided into five regions based on selectivity mechanism. These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core.
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