Identification of glycogen phosphorylase as molecular target for antidiabetic action of Nauclea latifolia Smith fruits

Type 2 Diabetes (T2D) is a metabolic disease characterized by a persistent increase in blood glucose above normal values due to a progressive insulin secretory defect. Diabetes is a leading cause of the pathophysiological conditions associated with the generation of reactive oxygen species and metabolic abnormalities resulting in microvascular and cardiovascular complications [1]. Glycogen phosphorylase (GP) has recently emerged as an important therapeutic target to discover potent antidiabetic drugs for T2D. We aimed to validate the traditional use of Nauclea latifolia (Rubiaceae) fruits as antidiabetic agent and identify its main chemical components, molecular target(s), and possible mechanism of action. Both the intact and processed fruits crude extract/fractions were screened for GP inhibition in vitro. Antioxidant activity was performed according to standard methods using DPPH and ABTS radicals compared with Ascorbic acid and Trolox. LC-PDA-ESIMS analysis and Molecular Operating Environment (MOE) were used for chemical profiling and in silico studies, respectively. Screening of N.latifolia fruits revealed a remarkable GP inhibition for the intact fruit (95.57%) compared to the processed fruit. The intact fruit ethyl acetate fraction exhibited the most prominent antioxidant activity which far exceeding its respective processed counterpart (89.50± 0.009, 83.57±0.02%RSA± SD,respectively). The chemical profiles of the fruits comprise β-carboline alkaloids and polyphenols. GP catalytic site was proved to be the most appropriate to accommodate alkaloids and phenolics identified in the fruits [Fig. 1].The intact fruit revealed superior antidiabetic and antioxidant capacity than the processed fruit. The catalytic site has been identified as the main molecular target.

Fig. 1 2D interaction of Strictosamide identified in N.latifolia intact (A) and processed (B) fruits with catalytic site of the GP

• References

• 1 Aydin A, Orhan H, Sayal A, O¨ zata M, Sahin G, Isımer A. Oxidative stress and nitric oxide related parameters in type II diabetes mellitus: effects of glycemic control. Clin Biochem. 2001; 34: 65-70.