Identification of flavonolignans from Silybum marianum seeds as allosteric protein tyrosine phosphatase 1B inhibitors

• Published in: Journal of Enzyme Inhibition and Medicinal Chemistry Vol. 33; no. 1; pp. 1283 - 1291
• Main Authors: Qin, Ningbo, Sasaki, Tatsunori, Li, Wei, Wang, Jian, Zhang, Xiangyu, Li, Dahong, Li, Zhanlin, Cheng, Maosheng, Hua, Huiming, Koike, Kazuo
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2018; Informa UK Limited; Taylor & Francis Group
• Subjects: Asteraceae; Asteraceae - chemistry; Dose-Response Relationship, Drug; Enzyme Inhibitors; Enzyme Inhibitors - analysis; Enzyme Inhibitors - pharmacology; flavonolignan; Flavonolignans; Flavonolignans - analysis; Flavonolignans - pharmacology; Humans; isosilybin; Molecular Docking Simulation; Molecular Structure; Protein tyrosine phosphatase 1B; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Research Paper; RM1-950; Seeds; Seeds - chemistry; silybin; Silybum marianum; Structure-Activity Relationship; Therapeutics. Pharmacology; Protein tyrosine phosphatase 1B; flavonolignan; Silybum marianum; isosilybin; silybin
• ISSN: 1475-6366; 1475-6374; 1475-6374
• DOI: 10.1080/14756366.2018.1497020

Protein tyrosine phosphatase 1B (PTP1B) is an attractive molecular target for anti-diabetes, anti-obesity, and anti-cancer drug development. From the seeds of Silybum marianum, nine flavonolignans, namely, silybins A, B (1, 2), isosilybins A, B (3, 4), silychristins A, B (5, 6), isosilychristin A (7), dehydrosilychristin A (8), and silydianin (11) were identified as a novel class of natural PTP1B inhibitors (IC 50 1.3 7-23.87 µM). Analysis of structure-activity relationship suggested that the absolute configurations at C-7" and C-8" greatly affected the PTP1B inhibitory activity. Compounds 1-5 were demonstrated to be non-competitive inhibitors of PTP1B based on kinetic analyses. Molecular docking simulations resulted that 1-5 docked into the allosteric site, including α3, α6, and α7 helix of PTP1B. At a concentration inhibiting PTP1B completely, compounds 1-5 moderately inhibited VHR and SHP-2, and weakly inhibited TCPTP and SHP-1. These results suggested the potentiality of these PTP1B inhibitors as lead compounds for further drug developments.