High-throughput screening has revealed dark chemical matter, a set of drug-like compounds that has never shown bioactivity despite being extensively assayed. If dark molecules are found active at a therapeutic target, their extraordinary selectivity profiles make excellent starting points for drug development. We explored if ligands of therapeutically relevant G-protein-coupled receptors could be discovered by structure-based virtual screening of the dark chemical matter. Molecular docking screens against crystal structures of the A2A adenosine and the D4 dopamine receptors were carried out, and 53 top-ranked molecules were evaluated experimentally. Two ligands of each receptor were discovered, and the most potent had sub-micromolar affinities. Analysis of bioactivity data showed that the ligands lacked activity at hundreds of off-targets, including several that are associated with adverse effects. Our results demonstrate that virtual screening provides an efficient means to mine the dark chemical space, which could contribute to development of drugs with improved safety profiles.

中文翻译：

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对接在暗化学物质中发现了GPCR配体。

高通量筛选显示了暗色化学物质，尽管经过广泛分析，但它们从未显示出生物活性，是一组类似药物的化合物。如果发现深色分子对治疗靶具有活性，则其非凡的选择性特征将为药物开发提供极好的起点。我们探索了是否可以通过对暗化学物质进行基于结构的虚拟筛选来发现治疗相关的G蛋白偶联受体的配体。针对A2A腺苷和D4多巴胺受体的晶体结构进行了分子对接筛选，并通过实验评估了53个排名最高的分子。发现每个受体的两个配体，并且最有效的具有亚微摩尔亲和力。对生物活性数据的分析表明，这些配体在数百个脱靶位上均缺乏活性，包括与不良影响相关的几种。我们的结果表明，虚拟筛选为挖掘黑暗的化学空间提供了一种有效的方法，这可能有助于开发具有改进安全性的药物。