Bromodomains (BrDs), a conserved structural module in chromatin-associated proteins, are well known for recognizing ε-N-acetyl lysine residues on histones. One of the most relevant BrDs is BRD4, a tandem BrD containing protein (BrD1 and BrD2) that plays a critical role in numerous diseases including cancer. Growing evidence shows that the two BrDs of BRD4 have different biological functions; hence selective ligands that can be used to study their functions are of great interest. Here, as a follow-up of our previous work, we first provide a detailed characterization study of the in silico rational design of Olinone as part of a series of five tetrahydropyrido indole-based compounds as BRD4 BrD1 inhibitors. Additionally, we investigated the molecular basis for Olinone's selective recognition by BrD1 over BrD2. Molecular dynamics simulations, free energy calculations, and conformational analyses of the apo-BRD4-BrD1|2 and BRD4-BrD1|2/Olinone complexes showed that Olinone's selectivity is facilitated by five key residues: Leu92 in BrD1|385 in BrD2 of ZA loop, Asn140|433, Asp144|His437 and Asp145|Glu438 of BC loop, and Ile146|Val49 of helix C. Furthermore, the difference in hydrogen bonds number and in mobility of the ZA and BC loops of the acetyl-lysine binding site between BRD4 BrD1/Olinone and BrD2/Olinone complexes also contribute to the difference in Olinone's binding affinity and selectivity toward BrD1 over BrD2. Altogether, our computer-aided molecular design techniques can effectively guide the development of small-molecule BRD4 BrD1 inhibitors, explain their selectivity origin, and further open doors to the design of new therapeutically improved derivatives.

中文翻译：

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Olinone 对 BRD4 的第一个溴结构域的选择性的计算机设计和分子基础。

Bromodomains (BrDs) 是染色质相关蛋白中的一个保守结构模块，以识别组蛋白上的 ε-N-乙酰赖氨酸残基而闻名。最相关的 BrD 之一是 BRD4，它是一种含有蛋白质（BrD1 和 BrD2）的串联 BrD，在包括癌症在内的多种疾病中起着关键作用。越来越多的证据表明 BRD4 的两个 BrD 具有不同的生物学功能；因此，可用于研究其功能的选择性配体引起了极大的兴趣。在这里，作为我们之前工作的后续工作，我们首先提供了 Olinone 的计算机合理设计的详细表征研究，作为一系列五种基于四氢吡啶并吲哚的化合物作为 BRD4 BrD1 抑制剂的一部分。此外，我们研究了 BrD1 相对于 BrD2 选择性识别 Olinone 的分子基础。分子动力学模拟，apo-BRD4-BrD1|2 和 BRD4-BrD1|2/Olinone 复合物的自由能计算和构象分析表明，Olinone 的选择性受到五个关键残基的促进：ZA 环的 BrD1|385 中的 Leu92，Asn140|433 ，BC环的Asp144|His437和Asp145|Glu438，以及螺旋C的Ile146|Val49。此外，BRD4 BrD1 / Olinone和BRD4之间乙酰赖氨酸结合位点的ZA和BC环的氢键数和迁移率的差异BrD2/Olinone 复合物也导致 Olinone 对 BrD1 的结合亲和力和选择性超过 BrD2 的差异。总而言之，我们的计算机辅助分子设计技术可以有效地指导小分子 BRD4 BrD1 抑制剂的开发，解释它们的选择性来源，并进一步为设计新的治疗改进衍生物打开大门。