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In-crystal affinity ranking of fragment hit compounds reveals a relationship with their inhibitory activities

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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
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)

Submitter: 田中 勲

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