综述：皂苷通过抑制肠道消化酶和微生物群相互作用的抗糖尿病作用机制及提高效能的计算机对接研究

《European Journal of Medicinal Chemistry》：Antidiabetic action mechanisms of saponins via gut digestive enzymes inhibition and microbiota interaction, a comprehensive review and in silico docking to improve efficacy

本综述系统阐述了皂苷类天然产物的抗糖尿病作用机制，重点聚焦于其对α-葡萄糖苷酶（α-glucosidase）和α-淀粉酶（α-amylase）的抑制作用、与肠道微生物群（Gut Microbiota）的相互作用，并借助计算机模拟对接（in silico docking）技术预测其结合模式，为开发高效抗糖尿病药物提供了新的研究视角和策略。

　　

Abstract:

Saponins are ubiquitous natural product class classified into triterpenoid and steroidal, where triterpenoid saponin mainly include dammaranes, oleananes, and ursanes, while steroidal saponins include furostane and spirostane with several health benefits. Saponins exert beneficial health effects including their role in diabetes management, targeting key cellular enzymes such as α-glucosidase and α-amylase, in addition to recent evidence for gut microbiota interaction to mediate for their antidiabetic action as summarized in this review. Further, analytical tools used for screening of α-glucosidase and α-amylase are compiled for researchers to decide on best assay types for the identification of inhibitors targeting these enzymes. This review focuses on saponins in context to their antidiabetic action, highlighting the impact of different structural motifs on their antihyperglycemic effect. Furthermore, in silico docking simulations were employed to predict the presumed binding modes of the reported bioactive saponins. Inhibitory activity of saponins appeared to be mostly influenced by glycosylation position, and the number of hydroxy groups. Oleanane saponins showed potential as antidiabetic agents among other saponin aglycones. More research is still needed to fully understand saponins′ action mechanisms, optimal dosage, and safety profile. Future investigations should focus towards optimizing saponins′ bioavailability to enhance their in vivo antidiabetic effects.

Introduction

Saponins represent a major class of phytoconstituent that exhibits a foamy quality upon agitation with water asides from their myriad of health benefits. Saponins encompass both water- and fat-soluble portions that account for most of their physicochemical and biological properties. Sapogenins represent the aglycone portion that are typically linked to one or more sugars or uronic acids moieties. There are several classes of saponins, but they can be broadly classified into two main groups based on their aglycone type: triterpenoid (C₃₀) and steroidal (C₂₇) saponins.

Triterpenoid saponins, the most widespread type of saponin derived from the triterpene squalene, is classified into two main subclasses: tetracyclic and pentacyclic triterpenes. Tetracyclic triterpenes include dammaranes the most common type of triterpenoid saponin found in plants such as yam, licorice, and soapwort. In contrast, pentacyclic triterpenes include lupanes (as in hops and soybeans), oleananes (as in ginseng and ginkgo biloba), and ursanes (as in comfrey). Oleanane and ursane are structural isomers which vary in the position of methyl group connected at either C-19 or C-20 position in their E ring. On the other hand, steroidal saponins are derived from cholesterol, and are less common than triterpenoid saponins, classified into two main subclasses: spirostane and furostane saponins. Spirostane saponin encompasses a spiroketal ring in its steroid nucleus such as in ginseng and Ginkgo biloba saponins. In contrast, furostanol saponins don’t encompass spiroketal ring, such as in licorice and soybeans saponins.

There are various degree of hydroxylation in aglycon moiety resulting in the wide spectrum of saponins. Mostly, hydroxyl group is present at C-3 position; often at C-16, C-21, and C-22 positions, and less often at C-2 and C-15 positions. The methyl group (at C-23, C-24, C-28, C-29, and C-30 positions) may be oxidized into CH₂OH, COOH, or CHO moieties. Epoxy groups, double bonds, and keto functions are present between C-12 and C-13 position. Esterified saponins are formed via acylation of their hydroxyl groups. With sugar moiety being attached mostly at C-3 and C-28 position via hydroxyl and carboxylic groups respectively, more than half of the triterpenoid saponins is widely distributed. In the next subsections, review of saponin rich extracts followed by individual saponin isolates assay is presented targeting α-glucosidase and α-amylase enzymes and further in context to their gut microbiota interaction and in silico docking analyses. Finally, a compile of the different analytical tools used for enzyme inhibition screening is presented to aid future researchers decide on best assay types for the identification of inhibitors targeting these enzymes.

Molecular docking study on α-glucosidase and α-amylase inhibitory saponins

Computational approaches, such as molecular docking enable the rapid screening of large chemical libraries or plant databases, predicting potential antidiabetic agents based on their binding affinity to the active site of enzymes. Docking simulations were performed employing the Molecular Orbital Environment (MOE) software. The coordinates of α-amylase (PDB ID: 7TAA) and α-glucosidase (PDB ID: 5ZCC) catalytic sites were used for the study. The inhibitory activity of saponins appeared to be mostly influenced by glycosylation position, and the number of hydroxy groups. Oleanane saponins showed potential as antidiabetic agents among other saponin aglycones, with their specific structural features allowing for favorable interactions within the enzyme active sites.

Conclusion

Saponins represent a diverse family of phytoconstituents found ubiquitous in planta. The wide chemical diversity of both triterpenoid and steroidal saponins has resulted in renewed interest in their potential effects especially antidiabetic action as reported in several saponin rich drugs such as licorice, soapwort, ginseng, and ginkgo biloba. Many saponins were reported to be antidiabetics through inhibition of digestive enzymes α-glucosidase and α-amylase. Asides from targeting digestive enzymes, interaction with gut microbiota represents another pivotal mechanism mediating saponins' antidiabetic effects. The structure-activity relationship studies and in silico docking analyses provide valuable insights for optimizing saponin structures to enhance their efficacy and bioavailability. Further research is warranted to fully elucidate their mechanisms of action, determine optimal dosage, and establish comprehensive safety profiles. Future investigations should prioritize strategies to improve the in vivo bioavailability of saponins to maximize their therapeutic potential in diabetes management.