Characterizations and Assays of α-Glucosidase Inhibition Activity on Gallic Acid Cocrystals: Can the Cocrystals be Defined as a New Chemical Entity During Binding with the α-Glucosidase?

Abstract

Cocrystallization with co-former (CCF) has proved to be a powerful approach to improve the solubility and even bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, it is still uncertain whether a cocrystal would exert the pharmacological activity in the form of a new chemical entity, an API-CCF supramolecule. In the present study, gallic acid (GA)-glutaric acid and GA-succinimide cocrystals were screened. The solubility, dissolution rate and oral bioavailability of the two cocrystals were evaluated. As expected, AUCs of GA-glutaric acid and GA-succinimide cocrystals were 1.86-fold and 2.60-fold higher than that of single GA, respectively. Moreover, experimental evaluations on α-glucosidase inhibition activity in vitro and theoretical simulations were used to detect whether the two cocrystals would be recognized as a new chemical entity during binding with α-glucosidase, a target protein in hypoglycemic mechanisms. The enzyme activity evaluation results showed that both GA and glutaric acid displayed α-glucosidase inhibition activity, and GA-glutaric acid cocrystals showed strengthened α-glucosidase inhibition activity at a moderate concentration, which is attributed to synergism of the two components. Molecular docking displayed that the GA-glutaric acid complex deeply entered the active cavity of the α-glucosidase in the form of a supramolecule, which made the guest-enzyme binding configuration more stable. For the GA and succinimide system, succinimide showed no enzyme inhibition activity, however, the GA-succinimide complex presented slightly higher α-glucosidase inhibition activity than that of GA. Molecular docking simulation indicated that the guest molecules entering the active cavity of the α-glucosidase were free GA and succinimide, not the GA-succinimide supramolecule.

Reusable Fluorescent Nanobiosensor Integrated in a Multiwell Plate for Screening and Quantification of Antidiabetic Drugs

“…The third compound, gallic acid, has recently been proposed as a potential inhibitor of this enzyme, alone or combined with acarbose. 50,51 The results displayed in Figure 6 support this finding and show that its inhibitory activity does not significantly differ from that of miglitol.…”

In situnet fishing of α-glucosidase inhibitors from evening primrose (Oenothera biennis) defatted seeds by combination of LC-MS/MS, molecular networking, affinity-based ultrafiltration, and molecular docking

“…All these results suggested that 1-galloyl-glucose, gallic acid, methyl gallate, 1,6-digalloyl-β- d -glucose, and 1,3,6-trigalloylglucose are potential α-glucosidase inhibitors. Previously, N. Xue et al 43 and R. Xu et al 44 reported that gallic acid and methyl gallate showed α-glucosidase inhibitory activities with IC 50 values of 2.79 mmol L −1 and 0.23 mg mL −1 , respectively. Moreover, the α-glucosidase inhibitory effect of 1,6-digalloyl-β- d -glucose was reported and its IC 50 was 0.16 mg mL −1 .…”

Pharmaceutical cocrystal and their role in improving solid state properties of active pharmaceutical ingredients

“…Hydrogen bindings (the main interaction), van der Waals forces as well as π-π interactions, which are noncovalent interactions are responsible for the development of cocrystals [9] . When the co crystal results from the conjugation an API with a pharmaceutically accepted excipient (known as co former), the resultant compound is known as pharmaceutical cocrystal [10] and as shown in Figure 1. [11] Advantages and limitation of cocrystals Owing to their advantages, cocrystals have become progressively widespread drug modifications.…”