Molecular insights into the inhibitory mechanism of dicoumaroylated flavonol rhamnosides on α-glucosidase

Autores

Pacheco Arce, T.M. (UNIVERSIDAD ICESI) ; Álvarez Caballero, J.M. (UNIVERSIDAD DEL MAGDALENA) ; Coy Barrera, E. (UNIVERSIDAD MILITAR NUEVA GRANADA) ; Escorcia Cabrera, A.M. (UNIVERSIDAD ICESI)

Resumo

α-glucosidase inhibitors currently available for treatment of Type II diabetes have undesired secondary effects. Therefore, the discovery of α-glucosidase inhibitors with diminished side effects is of great importance. In this work, molecular docking simulations were performed to model the formation of protein- ligand complexes between α-glucosidase and dicoumaroylated flavonol rhamnosides with experimentally proven inhibitory activity. The predicted complexes show binding affinity values that correlate qualitatively well with the IC₅₀ values determined experimentally. Structural analysis of these complexes led to the identification of protein-ligand interactions that are key for the inhibitory activity of the flavonol molecules.

Palavras chaves

Molecular docking; α-glucosidase; Diabetes

Introdução

There are about 425 million people with diabetes worldwide, Type II diabetes being the most predominant. α-glucosidase inhibitors slow the release of free glucose in the small intestines by inhibiting the hydrolysis of dietary carbohydrates, and so are used for treatment of Type II diabetes. However, comercially available α- glucosidase inhibitors such as acarbose induce undesired gastrointestinal side effects, such as abdominal bloating, cramping, increased flatulence, or diarrhea. Therefore, new α-glucosidase inhibitory drugs are required (Li et al, 2019; Turner et al, 2020). Recently, a set of dicoumaroylated flavonol rhamnosides have been reported to exhibit α-glucosidase inhibitory activities which are remarkably highger than that exhibited by acarbose (Li et al, 2019). However, the action mechanism of these molecules remains unknown. Therefore, in this study, we performed molecular docking simulations to get molecular information on the binding mechanism of these molecules and to identify the structural features that make them better inhibitors than acarbose. The results of our simulations are expected to help to the rational desing of new potent and selective α-glucosidase inhibitors with reduced side effects.

Material e métodos

The compounds addressed in this study are shown in Figure 1. The structures of these molecules were built with Marvin JS (Cherinka et al, 2019) and further optimized at the AM1 level using the Gaussian09 program (Frisch et al, 2016). After optimization, the structures were submitted to the DockThor server (Guedes et al, 2021) for docking simulations, with the crystal structure of α-glucosidase with PDB ID 3TOP (Ren et al, 2011) as a target. The docking simulations were performed under default conditions of the DockThor server. Ionizable protein residues were protonated considering standard protonation states at pH 7. Several docking experiments using different docking boxes were performed for each molecule. Except for compound 1, the α-glucosidase inhibitory activities (IC50) of the compounds studied here have been reported previously (Li et al, 2019). Moreover, the 3TOP crystal structure corresponds to the acarbose αglucosidase complex (Ren et al, 2011). Thus, acarbose was included in this study as a reference system to validate our docking approach, while compound 1 is the first attempt to use this approach as a predicting tool of inhibitory activity.

Resultado e discussão

The binding mode of acarbose in the 3TOP crystal structure and that predicted by docking with the best score are alike (Figure 2). Moreover, the docking simulations show that the flavonol compounds are able to form a higher number of complexes (9-14 complexes) with α-glucosidase than acarbose (4 complexes). Furthermore, overall the complexes of the flavonol compounds show higher binding affinity values (7.9 to -10.6 kcal/mol) than the acarbose complexes (-7.1 to -9.0 kcal/mol). These results correlate qualitatively well with the IC₅₀ values determined experimentally. While the IC₅₀ for acarbose is 266.1 μM, the flavonol compounds 2-4 display IC₅₀ values between 12 μM and 36 μM (Li et al, 2019). This shows the already known good performance of DockThor to predict the structure of protein-ligand complexes and suggests that it can be used to qualitatively assess/predict the αglucosidase inhibitory activity of compounds which have not been experimentally tested. Thus, compound 1 is expected to exhibit an inhibitory activity similar to compounds 2-4. Structural analysis of the complexes identified led to the identification of key protein-ligand interactions for α-glucosidase inhibitory activity.

Compounds studied in this work.


Superimposion of the α-glucosidase acarbose complex of the 3TOP crystal structure with the top scoring complex predicted by docking.

Conclusões

Dicoumaroylated flavonol rhamnosides are able to form a higher number of stable complexes with α‑glucosidase and display higher binding affinities than acarbose, which explains the difference observed for these compounds regarding IC50 values. Our docking simulations provide information that may help to the rational design of more potent and selective α-glucosidase inhibitors.

Agradecimentos

Referências

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