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?

Na Xue,Yutao Jia,Jing Wang,Binnan He,Congwei Li,Caiqin Yang

doi:10.3390/molecules25051163

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.

Highlights

Improving the solubility, dissolution rate and oral bioavailability of poorly soluble active pharmaceutical ingredients (API) is one of the main challenges in the pharmaceutical industry.A pharmaceutical cocrystal is a supramolecular system constructed using an API and a biocompatible small molecule through non-covalent forces involving hydrogen bonds and van der Waals forces
The solubility, dissolution, oral bioavailability and α-glucosidase inhibitory activity of gallic acid (GA) were improved through forming cocrystals with glutaric acid and succinimide
To the best of our knowledge, this study is the first to demonstrate the changes induced by cocrystals on the binding interaction of API with the targeting protein using experimental and molecule docking methods

Summary

Introduction

Dissolution rate and oral bioavailability of poorly soluble active pharmaceutical ingredients (API) is one of the main challenges in the pharmaceutical industry. A pharmaceutical cocrystal is a supramolecular system constructed using an API and a biocompatible small molecule (termed cocrystal former, CCF) through non-covalent forces involving hydrogen bonds and van der Waals forces. Cocrystallization with CCF has proved to be a powerful approach to tune the stability, solubility, dissolution rate, bioavailability, and mechanical properties of the poorly water-soluble API [1,2,3,4,5]. It is generally believed that the pharmacological activity of APIs is not changed by cocrystallization with a CCF. How the regulatory status of cocrystals is defined during the pharmacological performance of APIs is still unsettled [6,7]. It was reported that indomethacin-based cocrystals showed different transepithelial electrical resistance (TEER) values and the ability to permeate across

Methods

Results

Conclusion