| Title: | In-crystal affinity ranking of fragment hit compounds reveals a relationship with their inhibitory activities |
| Authors: | Yamane, Junji Browse this author |
| Yao, Min Browse this author |
| Zhou, Yong Browse this author |
| Hiramatsu, Yasuyuki Browse this author |
| Fujiwara, Kenichiro Browse this author |
| Yamaguchi, Tohru Browse this author |
| Yamaguchi, Hiroto Browse this author |
| Togame, Hiroko Browse this author |
| Tsujishita, Hideki Browse this author |
| Takemoto, Hiroshi Browse this author |
| Tanaka, Isao Browse this author |
| Issue Date: | Aug-2011 |
| Publisher: | International Union of Crystallography |
| Journal Title: | Journal of Applied Crystallography |
| Volume: | 44 |
| Issue: | 4 |
| Start Page: | 798 |
| End Page: | 804 |
| Publisher DOI: | 10.1107/S0021889811017717 |
| Abstract: | Fragment-based drug discovery (FBDD), which is a molecular build-up strategy from small scaffolds, has recently become a promising approach for lead-compound generation. Although high-throughput protein crystallography is usually used to determine the protein-ligand complex structure and identify potential hit compounds, the relationship between the quality of the Fo-Fc maps of hit compounds and their inhibitory activities has rarely been examined. To address this issue, crystallographic competition experiments were carried out to determine the relative order of the in-crystal binding affinities using five hit compounds of bovine pancreatic trypsin inhibitors. Soaking experiments of all combinations of the five hit compounds were used to define the in-crystal affinity ranking. Based on characterization by a high-concentration bioassay, a clear correlation was observed between in-crystal binding affinities and the inhibitory activities in solution. Moreover, the correlation analysis revealed that X-ray-based screening can detect a weak hit compound with inhibitory activity below the limit of detection, even in a high-concentration assay. The proposed crystallographic competition method could function as a valuable tool, not only to select a plausible starting scaffold for subsequent synthetic efforts but also to access structure-activity relationships using fragment compounds with a wider detection limit than a biological assay. The crystallographic validation methodology described here will greatly accelerate the hit-to-lead process during fragment-based and structure-based drug design. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/46908 |
| Appears in Collections: | 生命科学院・先端生命科学研究院 (Graduate School of Life Science / Faculty of Advanced Life Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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