The natural flavone fukugetin as a mixed-type inhibitor for human tissue kallikreins

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 5; pp. 1485 - 1489
• Main Authors: Santos, Jorge A.N., Kondo, Márcia Y., Freitas, Renato F., dos Santos, Marcelo H., Ramalho, Teodorico C., Assis, Diego M., Juliano, Luiz, Juliano, Maria A., Puzer, Luciano
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2016
• Subjects: Biflavonoids - chemistry; Biflavonoids - isolation & purification; Biflavonoids - pharmacology; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Dose-Response Relationship, Drug; Enzyme; Flavone; Garcinia - chemistry; Humans; Inhibitor; Kallikrein; Models, Molecular; Molecular Conformation; Molecular docking; Molecular dynamic simulation; Serine protease; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - isolation & purification; Serine Proteinase Inhibitors - pharmacology; Structure-Activity Relationship; Tissue Kallikreins - antagonists & inhibitors; Tissue Kallikreins - metabolism; Enzyme; Flavone; Kallikrein; Serine protease; Inhibitor; Molecular dynamic simulation; Molecular docking
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.01.039

[Display omitted] The human tissue kallikreins (KLK1–KLK15) comprise a family of 15 serine peptidases detected in almost every tissue of the human body and that actively participate in many physiological and pathological events. Some kallikreins are involved in diseases for which no effective therapy is available, as for example, epithelial disorders, bacterial infections and in certain cancers metastatic processes. In recent years our group have made efforts to find inhibitors for all kallikreins, based on natural products and synthetic molecules, and all the inhibitors developed by our group presented a competitive mechanism of inhibition. Here we describe fukugetin, a natural product that presents a mixed-type mechanism of inhibition against KLK1 and KLK2. This type of inhibitor is gaining importance today, especially for the development of exosite-type inhibitors, which present potential to selectively inhibit the enzyme activity only against specific substrate.