A rapid and practical approach for the discovery of new chemical matter for targeting pathogens and diseases is described. Fragment‐based phenotypic lead discovery (FPLD) combines aspects of traditional fragment‐based lead discovery (FBLD), which involves the screening of small‐molecule fragment libraries to target specific proteins, with phenotypic lead discovery (PLD), which typically involves the screening of drug‐like compounds in cell‐based assays. To enable FPLD, a diverse library of fragments was first designed, assembled, and curated. This library of soluble, low‐molecular‐weight compounds was then pooled to expedite screening. Axenic cultures of Leishmania promastigotes were screened, and single hits were then tested for leishmanicidal activity against intracellular amastigote forms in infected murine bone‐marrow‐derived macrophages without evidence of toxicity toward mammalian cells. These studies demonstrate that FPLD can be a rapid and effective means to discover hits that can serve as leads for further medicinal chemistry purposes or as tool compounds for identifying known or novel targets.

中文翻译：

---

基于片段的表型先导发现：靶向利什曼病的基于细胞的分析

描述了一种快速实用的方法，用于发现针对病原体和疾病的新化学物质。基于片段的表型先导发现（FPLD）结合了传统的基于片段的先导发现（FBLD）的各个方面，其中涉及筛选针对特定蛋白质的小分子片段文库，以及通常涉及筛选的表型先导发现（PLD）基于细胞的测定中的类药物化合物的分析。为了启用FPLD，首先设计，组装和管理了多样化的片段库。然后将这个可溶的低分子量化合物文库合并以加快筛选。利什曼原虫的焦虑症文化筛选前鞭毛体，然后测试单次命中对感染的鼠源性骨髓巨噬细胞中胞内鞭毛体形式的杀螨活性，而没有证据表明对哺乳动物细胞有毒性。这些研究表明，FPLD可以是发现命中物的快速有效的手段，这些命中物可以用作进一步的药物化学用途的线索，也可以作为鉴定已知或新靶标的工具化合物。