A theoretical insight into selectivity of inhibitors toward two domains of bromodomain‐containing protein 4 using molecular dynamics simulations,Chemical Biology & Drug Design

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A theoretical insight into selectivity of inhibitors toward two domains of bromodomain‐containing protein 4 using molecular dynamics simulations
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2017-12-10 , DOI: 10.1111/cbdd.13148
Jing Su ₁ , Xinguo Liu ₁ , Shaolong Zhang ₁ , Fangfang Yan ₁ , Qinggang Zhang ₁ , Jianzhong Chen ₂

Affiliation

Bromodomains (BRDs) have been an attractive candidate for development of efficient inhibitors toward gene transcription. Molecular dynamics (MD) simulations followed by principal component (PC) analysis were performed to investigate binding selectivity of inhibitors RVX297, BSP, JQ1, SF2523, and CPD2 toward two domains (BD1 and BD2) of bromodomain‐containing protein 4 (BRD4). The results show that inhibitor bindings exert different effect on motions of the BC‐loops in BD1 and BD2. The rank of binding free energies calculated using molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA) method agrees with the one determined by experiment. The results also suggest that the binding ability of RVX297, BSP, and JQ1 to BD2 is stronger than that of them to BD1, while the binding ability of SF2523 to BD2 is obviously weaker than that of SF2523 to BD1. Alanine mutation calculations and the calculated inhibitor–residue interaction spectrum prove that the current five inhibitors have obvious binding selectivity toward BD1 and BD2. This study is not only helpful for further understanding the differences in internal dynamics of BD1 and BD2 caused by inhibitor bindings, but also can theoretically contribute significant guidance to designs of effective and high selective anticancer drugs targeting BD1 and BD2 in BRD4.

中文翻译：

使用分子动力学模拟理论研究抑制剂对含溴结构域蛋白4的两个结构域的选择性

溴结构域（BRD）已成为开发有效的抑制基因转录抑制剂的诱人候选物。进行了分子动力学（MD）模拟，然后进行主成分（PC）分析，以研究抑制剂RVX297，BSP，JQ1，SF2523和CPD2对含溴结构域蛋白4（BRD4）的两个结构域（BD1和BD2）的结合选择性。结果表明抑制剂结合对BD1和BD2中BC环的运动产生不同的影响。用分子力学泊松-玻尔兹曼表面积（MM-PBSA）方法计算的结合自由能等级与实验确定的等级一致。结果还表明，RVX297，BSP和JQ1与BD2的结合能力强于RV2297，BSP和JQ1与BD1的结合能力，而SF2523与BD2的结合能力明显弱于SF2523与BD1的结合能力。丙氨酸突变计算和计算的抑制剂-残基相互作用谱证明，目前的五种抑制剂对BD1和BD2具有明显的结合选择性。这项研究不仅有助于进一步了解抑制剂结合引起的BD1和BD2内部动力学的差异，而且在理论上可以为设计针对BRD4中BD1和BD2的有效和高选择性抗癌药物提供重要指导。

更新日期：2017-12-10

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