State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Road, Qingdao 266237, Shandong, P. R. China.
J Med Chem. 2021 Aug 12;64(15):10581-10605. doi: 10.1021/acs.jmedchem.1c00683. Epub 2021 Jul 27.
The development of multitarget-directed ligands (MTDLs) has become a widely focused research topic, but rational design remains as an enormous challenge. This paper reviews and discusses the design strategy of incorporating the second activity into an existing single-active ligand. If the binding sites of both targets share similar endogenous substrates, MTDLs can be designed by merging two lead compounds with similar functional groups. If the binding sites are large or adjacent to the solution, two key pharmacophores can be fused directly. If the binding regions are small and deep inside the proteins, the linked-pharmacophore strategy might be the only way. The added pharmacophores of second targets should not affect the binding mode of the original ones. Moreover, the inhibitory activities of the two targets need to be adjusted to achieve an optimal ratio.
多靶点导向配体（MTDLs）的开发已成为一个广泛关注的研究课题，但合理设计仍然是一个巨大的挑战。本文综述并讨论了将第二种活性引入现有单活性配体的设计策略。如果两个靶点的结合位点共享类似的内源性底物，则可以通过将具有相似官能团的两种先导化合物合并来设计 MTDLs。如果结合位点较大或位于溶液附近，则可以直接融合两个关键药效团。如果结合区域较小且位于蛋白质内部深处，则链接药效团策略可能是唯一的方法。第二个目标的附加药效团不应影响原始药效团的结合模式。此外，需要调整两个靶点的抑制活性以达到最佳比例。
