Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, China.
Molecules. 2021 Dec 26;27(1):118. doi: 10.3390/molecules27010118.
Bromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targeting androgen-receptor (AR)-driven cancers. In order to explore the effect of inhibitors binding to BRD4 (the most studied member of BET family), four 150 ns molecular dynamic simulations were performed (free BRD4, Cpd4-BRD4, Cpd9-BRD4 and Cpd19-BRD4). Docking studies showed that Cpd9 and Cpd19 were located at the active pocket, as well as Cpd4. Molecular dynamics (MD) simulations indicated that only Cpd19 binding to BRD4 can induce residue Trp81-Ala89 partly become α-helix during MD simulations. MM-GBSA calculations suggested that Cpd19 had the best binding effect with BRD4 followed by Cpd4 and Cpd9. Computational alanine scanning results indicated that mutations in Phe83 made the greatest effects in Cpd9-BRD4 and Cpd19-BRD4 complexes, showing that Phe83 may play crucial roles in Cpd9 and Cpd19 binding to BRD4. Our results can provide some useful clues for further BCPs family search.
溴结构域和末端结构域（BET）亚家族是溴结构域蛋白（BCP）家族中研究最多的亚家族，它可以调节乙酰化信号转导并产生多种生理功能。因此，BET 家族可以作为针对雄激素受体（AR）驱动的癌症的替代策略。为了研究抑制剂与 BRD4（BET 家族中研究最多的成员）结合的效果，进行了四次 150ns 的分子动力学模拟（游离 BRD4、Cp d4-BRD4、Cp d9-BRD4 和 Cp d19-BRD4）。对接研究表明，Cp d9 和 Cp d19 位于活性口袋中，Cp d4 也是如此。分子动力学（MD）模拟表明，只有 Cp d19 与 BRD4 结合才能在 MD 模拟过程中诱导残基 Trp81-Ala89 部分变成α-螺旋。MM-GBSA 计算表明，Cp d19 与 BRD4 的结合效果最好，其次是 Cp d4 和 Cp d9。计算丙氨酸扫描结果表明，突变 Phe83 在 Cp d9-BRD4 和 Cp d19-BRD4 复合物中产生的影响最大，表明 Phe83 可能在 Cp d9 和 Cp d19 与 BRD4 结合中发挥关键作用。我们的结果可以为进一步研究 BCPs 家族提供一些有用的线索。
