期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 24, 页码 13331-13342出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202100273
关键词
crystallographic fragment screening; microtubules; molecular dynamics simulation; protein– ligand interactions; tubulin
资金
- iNEXT - Horizon 2020 program of the European Union [PID2692]
- Regione Lombardia [239047 NEON]
- Swiss National Science Foundation [31003A_166608, 310030_192566]
- Swiss National Science Foundation (SNF) [310030_192566] Funding Source: Swiss National Science Foundation (SNF)
Using a combined computational and crystallographic approach, researchers identified 27 distinct binding sites in tubulin, including 11 previously unknown sites. They also observed an intricate pocket communication network and identified 56 chemically diverse fragments that bound to 10 distinct tubulin sites. These results provide a structural basis for developing novel small molecules as tubulin modulators and lay down a framework that may aid in discovering new pockets in other pharmaceutically important targets.
Tubulin plays essential roles in vital cellular activities and is the target of a wide range of proteins and ligands. Here, using a combined computational and crystallographic fragment screening approach, we addressed the question of how many binding sites exist in tubulin. We identified 27 distinct sites, of which 11 have not been described previously, and analyzed their relationship to known tubulin-protein and tubulin-ligand interactions. We further observed an intricate pocket communication network and identified 56 chemically diverse fragments that bound to 10 distinct tubulin sites. Our results offer a unique structural basis for the development of novel small molecules for use as tubulin modulators in basic research applications or as drugs. Furthermore, our method lays down a framework that may help to discover new pockets in other pharmaceutically important targets and characterize them in terms of chemical tractability and allosteric modulation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据