Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, MA, 02143, USA.
Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK.
J Comput Aided Mol Des. 2018 Apr;32(4):573-582. doi: 10.1007/s10822-018-0113-2. Epub 2018 Mar 26.
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.
CCR9 拮抗作用是治疗炎症性肠病（包括溃疡性结肠炎和克罗恩病）的一种有前途的机制。由于 CCR9 及其配体的实验数据有限，这使得识别新的小分子拮抗剂的工作变得复杂。我们在此介绍了一项成功的虚拟筛选和合理的从头开始药物研发活动的结果，该活动导致发现和初步优化了新型 CCR9 拮抗剂。这项工作使用了一种新颖的数据融合策略，将多个计算工具（如 2D 相似性搜索、形状相似性、药效团搜索和分子对接）的输出以及特权趋化因子片段的识别和整合进行集成。各种排名策略的应用，结合了共识和并行选择方法，以实现富集和新颖性之间的平衡，总共产生了 198 个虚拟筛选命中，总命中率为 18%。通过有针对性的合成和购买类似物，对几个命中物进行了早期开发。
