Discovery of hyaluronidase inhibitors from natural products and their mechanistic characterization under DMSO-perturbed assay conditions

Keisuke Tomohara, Tomohiro Ito, Saika Onikata, Atsushi Kato, Isao Adachi

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1620-1623
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number7
DOIs
Publication statusPublished - Jan 1 2017
Externally publishedYes

Fingerprint

Hyaluronoglucosaminidase
Catechin
Dimethyl Sulfoxide
Biological Products
Assays
Panax
Molecules
Enzyme Inhibitors
Enzymes
Hyaluronic Acid
Drug Discovery
Biological Assay
Catalytic Domain
Screening
Binding Sites

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Discovery of hyaluronidase inhibitors from natural products and their mechanistic characterization under DMSO-perturbed assay conditions. / Tomohara, Keisuke; Ito, Tomohiro; Onikata, Saika; Kato, Atsushi; Adachi, Isao.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 7, 01.01.2017, p. 1620-1623.

Research output: Contribution to journalArticle

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