Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. These results reveal AutoCouple as a useful in silico coupling method to expand the chemical space in hit optimization campaigns resulting in potent, selective, and cell permeable bromodomain ligands.

中文翻译：

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在计算机模拟虚拟偶联（AutoCouple）指导下的溴结构域配体的化学空间扩展

扩大化学空间并同时确保合成的可及性是最重要的，这不仅对于发现新型蛋白质的有效结合剂，而且对于开发针对难于药物的蛋白质的化合物更重要。在这里，我们介绍了AutoCouple，这是一种从头开始的计算配体设计方法，重点在于通过虚拟耦合对化学实体进行多样性导向的生成。在一个基准应用中，通过合成原始片段的约50种衍生物，获得了对CBP溴结构域具有低纳摩尔效价且对BRD4（1）溴结构域具有高选择性的化学多样性化合物。通过X射线晶体学确认了结合模式，证明了细胞中的靶标结合，并且在三种癌细胞系中展示了抗增殖活性。