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

Journal of Enzyme Inhibition and Medicinal Chemistry
Ning-Bo QinKazuo Koike

Abstract

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 (IC50 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.

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Citations

Feb 13, 2020·Natural Product Reports·Marjorie BruderDaniela B B Trivella
Feb 9, 2021·Critical Reviews in Food Science and Nutrition·Carina ProençaEduarda Fernandes
Aug 8, 2021·International Journal of Molecular Sciences·Vladimír Křen
Oct 14, 2020·Journal of Agricultural and Food Chemistry·Xin WangShuai-Cheng Wu

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Methods Mentioned

BETA
X-ray

Software Mentioned

CHARMm
Biovia Discovery Studio
DOCKER
CDOCKER

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