Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 27, Issue 7, Pages 1620-1623Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.01.083
Keywords
Hyaluronidase inhibitor; Non-specific binding; DMSO; Concentration-response curve; Catechin
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Funding
- JSPS KAKENHI Grant [JP26870217]
- Tamura Science and Technology Foundation
- Grants-in-Aid for Scientific Research [26870217] Funding Source: KAKEN
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The present study discovered four novel hyaluronan-degrading enzyme (hyaluronidase) inhibitors including chikusetsusaponins and catechins through the activity-guided separation of Panax japonicus and Prunus salicina, respectively. Although the discovery resulted in identification of usual frequent hitters, subsequent mechanistic characterizations under our DMSO-perturbed assay conditions and related protocols revealed that chikusetusaponin IV would serve as an aggregating and non-specific binding inhibitor, while (-)-epicatechin would interact specifically with enzyme at the catalytic site or more likely at a kind of catechin-binding site with a relatively week inhibitory activity. The latter description might provide a possible explanation for the well-known fact that a series of catechin have been described as frequent hitters in biological assays with a moderate activity. Thus, the present study demonstrated a practical and robust methodology to characterize initial screening hits mechanistically molecule-by-molecule in the early stage of natural product-based drug discovery. (C) 2017 Elsevier Ltd. All rights reserved.
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