Inhibition of Aldose Reductase by Ginsenoside Derivatives via a Specific Structure Activity Relationship with Kinetics Mechanism and Molecular Docking Study

Abstract

This present work is designed to evaluate the anti-diabetic potential of 22 ginsenosides via the inhibition against rat lens aldose reductase (RLAR), and human recombinant aldose reductase (HRAR), using DL-glyceraldehyde as a substrate. Among the ginsenosides tested, ginsenoside Rh2, (20S) ginsenoside Rg3, (20R) ginsenoside Rg3, and ginsenoside Rh1 inhibited RLAR significantly, with IC50 values of 0.67, 1.25, 4.28, and 7.28 µM, respectively. Moreover, protopanaxadiol, protopanaxatriol, compound K, and ginsenoside Rh1 were potent inhibitors of HRAR, with IC50 values of 0.36, 1.43, 2.23, and 4.66 µM, respectively. The relationship of structure–activity exposed that the existence of hydroxyl groups, linkages, and their stereo-structure, as well as the sugar moieties of the ginsenoside skeleton, represented a significant role in the inhibition of HRAR and RLAR. Additional, various modes of ginsenoside inhibition and molecular docking simulation indicated negative binding energies. It was also indicated that it has a strong capacity and high affinity to bind the active sites of enzymes. Further, active ginsenosides suppressed sorbitol accumulation in rat lenses under high-glucose conditions, demonstrating their potential to prevent sorbitol accumulation ex vivo. The findings of the present study suggest the potential of ginsenoside derivatives for use in the development of therapeutic or preventive agents for diabetic complications.

Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target

“…From these data, it is predicted that GdAldRed is a viable target of LL and that LL presented a better binding affinity in the active site. In a review of studies of enzyme inhibition by terpene compounds, it was found that several members of the terpene family, such as ginsenosides (triterpene saponins), perillosides A and C (monoterpene glycosides) and triterpenes/meroterpenes from Ganodema lucidium (lanostane and farnesyl hydroquinone-triterpene conjugates), have the ability to inhibit AldRed from humans and other species [18][19][20][21]. This prompted us to predict whether the diterpene LL was able to interact and inhibit GdAldRed using molecular docking approaches.…”

Comparative Characterization of the Ginsenosides from Six Panax Herbal Extracts and Their In Vitro Rat Gut Microbial Metabolites by Advanced Liquid Chromatography–Mass Spectrometry Approaches

“…In previous studies, the 24(S)-OT saponins, vinaginsenoside R2, and majonoside R2 were metabolized to pseudoginsenoside RT4 cultured with mouse feces. 47 Generally, CK and Rh1 are the main metabolites of PPD or PPT-type ginsenosides, which have been reported to exhibit anti-inflammatory, 48 antioxidant, 7 antidiabetic, 6 antihypertension, 10 and other biological activities. The pharmacokinetic study unveiled that the metabolism capacity of the ginsenosides (such as the generation of CK) varied significantly among individuals.…”

“…Several categories of phytochemicals have been reported or isolated from the valuable Panax species. However, ginsenosides are regarded as the main bioactive ingredients, exhibiting antidiabetic, , anticancer, anti-inflammatory, antihypertensive, , and lipid-lowering effects . Consequently, they function as chemical markers for the quality control of ginseng. − To compare the nature and content differences of different ginsenosides (qualitatively/quantitatively) among different ginseng extracts, as well as the differences in their metabolites generated by the intestinal microbiota, a profound understanding of their functional differentiations is paramount.…”

6-Formyl Umbelliferone, a Furanocoumarin from Angelica decursiva L., Inhibits Key Diabetes-Related Enzymes and Advanced Glycation End-Product Formation

“…Aldose reductase (AR, EC 1.1.1.21) is a key aldo-keto reductase enzyme of the polyol pathway that catalyzes glucose to sorbitol, along with the parallel conversion of NADPH to NADP + [ 15 ]. Furthermore, sorbitol is converted to fructose by the presence of the sorbitol dehydrogenase enzyme, and that occurs in an NAD + -dependent manner [ 16 ]. AR is known to play key roles in the pathogenesis of diabetes-related complications such as neuropathy, nephropathy, and retinopathy [ 17 ].…”

“…AR is known to play key roles in the pathogenesis of diabetes-related complications such as neuropathy, nephropathy, and retinopathy [ 17 ]. AR inhibitors, which are critical for managing factors involved in the onset and progression of DM, are also being developed [ 16 ]. Therefore, AR is an attractive target for researchers who are designing and developing drugs to treat and manage long-term diabetic complications.…”