Discovery of hyaluronidase inhibitors from natural products and their mechanistic characterization under DMSO-perturbed assay conditions. Issue 7 (1st April 2017)

• Record Type: Journal Article
• Authors: Tomohara, Keisuke; Ito, Tomohiro; Onikata, Saika; Kato, Atsushi; Adachi, Isao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 7(2017)
• Page Start: 1620
• Page End: 1623
• Publication Date: 2017-04-01
• Subjects: Hyaluronidase inhibitor -- Non-specific binding -- DMSO -- Concentration-response curve -- Catechin; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.01.083
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.