Discoidin domain receptor 1 (DDR1) inhibitors with a desired pharmacophore were designed using deep generative models (DGMs). DDR1 is a receptor tyrosine kinase activated by matrix collagens and implicated in diseases such as cancer, fibrosis and hypoxia. Herein we describe the synthesis and inhibitory activity of compounds generated from DGMs. Three compounds were found to have sub‐micromolar inhibitory activity. The most potent of which, compound 3 (N‐(4‐chloro‐3‐((pyridin‐3‐yloxy)methyl)phenyl)‐3‐(trifluoromethyl)benzamide), had an IC₅₀ value of 92.5 nM. Furthermore, these compounds were predicted to interact with DDR1, which have a desired pharmacophore derived from a known DDR1 inhibitor. The results of synthesis and experiments indicated that our de novo design strategy is practical for hit identification and scaffold hopping.

中文翻译：

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使用深度生成模型设计和合成具有所需药效团的 DDR1 抑制剂

使用深度生成模型 (DGM) 设计具有所需药效团的盘状蛋白结构域受体 1 (DDR1) 抑制剂。DDR1 是一种由基质胶原激活的受体酪氨酸激酶，与癌症、纤维化和缺氧等疾病有关。在此，我们描述了由 DGM 产生的化合物的合成和抑制活性。发现三种化合物具有亚微摩尔抑制活性。其中最有效的化合物3（N-（4-氯-3-（（吡啶-3-基氧基）甲基）苯基）-3-（三氟甲基）苯甲酰胺）的 IC ₅₀值为 92.5 nM。此外，预测这些化合物会与 DDR1 相互作用，DDR1 具有源自已知 DDR1 抑制剂的所需药效团。合成和实验结果表明我们的从头设计策略对于命中识别和支架跳跃是实用的。