loading . . . Analogues of Dihydroflavonol and Flavone as Protein Tyrosine Phosphatase 1B Inhibitors from the Leaves of Artocarpus elasticus Protein tyrosine phosphatase 1B (PTP1B) is one of the target enzymes whose disruption leads to obesity and diabetes. A series of PTP1B inhibitors were isolated from the leaves of Artocarpus elasticus, used in traditional medicines for diabetes. The isolated inhibitors (1ā13), including two new compounds (1 and 2), consisted of dihydroflavonols and flavones. The structural requirements for the PTP1B inhibitory mode and potency were revealed in both skeletons. The two highest PTP1B inhibitory properties were dihydroflavonol 1 and flavone 6 analogs with IC50 values of 0.17 and 0.79 Ī¼M, respectively. The stereochemistry also affected inhibitory potencies: trans isomer 1 (IC50= 0.17 Ī¼M) vs cis isomer 2 (IC50= 2.24 Ī¼M). Surprisingly, the dihydroflavonol and flavone glycosides (11 and 13) displayed potent inhibition with IC50s of 2.39 and 0.22 Ī¼M, respectively. Furthermore, competitive inhibitor 1 was applied to time-dependence experiments as a simple slow-binding inhibitor with parameters of Kiapp = 0.064103 Ī¼M, k3 = 0.2262 Ī¼Mā1 minā1, and k4 = 0.0145 minā1. The binding affinities by using the fluorescence quenching experiment were highly correlated with inhibitory potencies: 1 (IC50= 0.17 Ī¼M, KSV = 0.4375 Ć 105 LĀ·molā1) vs 3 (IC50= 17.79 Ī¼M, KSV = 0.0006 Ć 105 LĀ·molā1). The specific binding interactions were estimated at active and allosteric sites according to the inhibitory mode by molecular docking. https://pubs.acs.org/doi/full/10.1021/acsomega.3c07471
