Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.

中文翻译：

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电子指导的新型CCR9拮抗剂的发现。

CCR9的拮抗作用是治疗炎症性肠病（包括溃疡性结肠炎和克罗恩氏病）的一种有前途的机制。有关CCR9及其配体的实验数据有限，使鉴定新的小分子拮抗剂的工作变得复杂。我们在这里介绍了成功的虚拟筛选和合理的铅对铅运动的结果，该运动导致了新型CCR9拮抗剂的发现和初步优化。这项工作使用一种新颖的数据融合策略来集成多种计算工具的输出，例如2D相似性搜索，形状相似性，药效基团搜索和分子对接以及特权趋化因子片段的识别和整合。运用各种排名策略，该方法结合了共识和并行选择方法，以实现丰富性和新颖性之间的平衡，总共产生了198个虚拟筛选匹配，总匹配率为18％。通过有针对性的合成和购买类似物，一些热门产品已发展为早期的领先者。