Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue Str. 9, 60438, Frankfurt, Germany.
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596, Frankfurt, Germany.
ChemMedChem. 2021 Apr 8;16(7):1088-1092. doi: 10.1002/cmdc.202000858. Epub 2021 Feb 4.
Designed multitarget ligands are a popular approach to generating efficient and safe drugs, and fragment-based strategies have been postulated as a versatile avenue to discover multitarget ligand leads. To systematically probe the potential of fragment-based multiple ligand discovery, we have employed a large fragment library for comprehensive screening on five targets chosen from proteins for which multitarget ligands have been successfully developed previously (soluble epoxide hydrolase, leukotriene A4 hydrolase, 5-lipoxygenase, retinoid X receptor, farnesoid X receptor). Differential scanning fluorimetry served as primary screening method before fragments hitting at least two targets were validated in orthogonal assays. Thereby, we obtained valuable fragment leads with dual-target engagement for six out of ten target combinations. Our results demonstrate the applicability of fragment-based approaches to identify starting points for polypharmacological compound development with certain limitations.
设计多靶标配体是生成高效和安全药物的一种流行方法，而基于片段的策略被认为是发现多靶标配体先导物的通用途径。为了系统地探索基于片段的多配体发现的潜力，我们使用了一个大型的片段库，对从以前成功开发多靶标配体的蛋白质中选择的五个靶标进行了全面筛选（可溶性环氧化物水解酶、白三烯 A4 水解酶、5-脂加氧酶、视黄醇 X 受体、法尼醇 X 受体）。差示扫描荧光法作为主要筛选方法，然后在正交测定中验证至少能与两个靶标结合的片段。由此，我们从十个靶标组合中的六个中获得了具有双重靶标结合的有价值的片段先导物。我们的结果表明，基于片段的方法在确定多药效化合物开发的起点方面具有一定的局限性，但具有适用性。
