Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy.
Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy.
Molecules. 2024 Aug 26;29(17):4025. doi: 10.3390/molecules29174025.
A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays. Compounds , , and showed high affinity for BRD4, with IC values of 0.60 ± 0.25 µM, 3.46 ± 1.22 µM, and 4.66 ± 0.52 µM, respectively. Additionally, these compounds were tested against two other bromodomains, BRD3 and BRD9, and two of them showed high selectivity for BRD4. The reported 3D structure-based pharmacophore model proves to be a straightforward and useful tool for selecting novel BRD4 ligands.
本文报道了一种基于 3D 结构的溴结构域蛋白 4（BRD4）药效团模型，该模型是专门为研究和确定 BRD4 结合部位中已知抑制剂（+）-JQ1 的关键结构特征而开发的。利用该药效团模型，对 273 种先前考虑用于其他靶点但效果不佳的合成和购买的化合物进行了药物重定位筛选。随后，仅有 6 种化合物显示出作为 BRD4 结合物的潜力，并进一步进行了生物物理和生化测定。化合物 、 和 对 BRD4 具有高亲和力，IC 值分别为 0.60 ± 0.25 µM、3.46 ± 1.22 µM 和 4.66 ± 0.52 µM。此外，这些化合物还针对另外两个溴结构域 BRD3 和 BRD9 进行了测试，其中两种化合物对 BRD4 具有高选择性。所报道的基于 3D 结构的药效团模型被证明是一种用于选择新型 BRD4 配体的直接而有用的工具。
