Centre for Integrative Biology, University of Trento, via Sommarive 9, 38123, Povo-Trento, Italy.
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
ChemMedChem. 2018 Jul 18;13(14):1479-1487. doi: 10.1002/cmdc.201800234. Epub 2018 Jun 21.
The bromodomain-containing protein BAZ2A is a validated target in prostate cancer research, whereas the function of its paralogue BAZ2B is still undefined. The bromodomains of BAZ2A and BAZ2B have a similar binding site for their natural ligand, the acetylated lysine side chain. Here, we present an analysis of the binding modes of eight compounds belonging to three distinct chemical classes. For all compounds, the moiety mimicking the natural ligand engages in essentially identical interactions in the BAZ2A and BAZ2B bromodomains. In contrast, the rest of the molecule is partially solvent-exposed and adopts different orientations with different interactions in the two bromodomains. Some of these differences could be exploited for designing inhibitors with selectivity within the BAZ2 bromodomain subfamily.
BRD 结构域蛋白 BAZ2A 是前列腺癌研究中经过验证的靶点，而其同源物 BAZ2B 的功能尚未确定。BAZ2A 和 BAZ2B 的 BRD 结构域具有相似的天然配体乙酰化赖氨酸侧链的结合位点。在这里，我们分析了属于三个不同化学类别的八种化合物的结合模式。对于所有化合物，模拟天然配体的部分在 BAZ2A 和 BAZ2B 的 BRD 结构域中基本相同。相比之下，分子的其余部分部分暴露在溶剂中，并在两个 BRD 结构域中采用不同的取向和不同的相互作用。这些差异中的一些可以被利用来设计在 BAZ2 溴结构域亚家族内具有选择性的抑制剂。
