Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai, China.
Nature. 2019 Feb;566(7743):224-229. doi: 10.1038/s41586-019-0917-9. Epub 2019 Feb 6.
Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC β-lactamase (AmpC) and the D dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D dopamine receptor.
尽管人们对拓展化学空间有着浓厚的兴趣，但包含数亿至数十亿种不同分子的库仍然难以获取。在这里，我们研究了基于结构的对接，使用 130 个特征明确的反应生成了 1.7 亿个按需合成的化合物。由此产生的库具有多样性，代表了超过 1070 万个其他无法获得的支架。我们模拟了库中每个化合物与 AmpC β-内酰胺酶（AmpC）和 D 多巴胺受体的对接。从排名最高的分子中，合成了 44 个和 549 个化合物，分别用于测试与 AmpC 和 D 多巴胺受体的相互作用。我们发现了一种 AmpC 的酚盐抑制剂，它揭示了一组以前未知的抑制剂。对这种分子进行了优化，得到了 77 nM 的抑制效果，使其成为已知最有效的非共价 AmpC 抑制剂之一。该抑制剂和其他 AmpC 抑制剂的晶体结构证实了对接预测。对于 D 多巴胺受体，命中率几乎随着对接得分单调下降，而命中率与得分曲线预测该库包含 453,000 个 D 多巴胺受体配体。在 81 个新发现的化学型中，有 30 个显示出亚微摩尔的活性，包括 D 多巴胺受体的 180 pM 亚型选择性激动剂。
