Screening of potential antidiabetic phytochemicals from Gongronema latifolium leaf against therapeutic targets of type 2 diabetes mellitus: multi-targets drug design

Abstract

Diabetes mellitus (DM) is the most predominant group of metabolic disorders wreaking havoc on the wellbeing of man, with type 2 diabetes mellitus (type 2 DM) accounting for most DM related cases. This study, hence, investigated the antidiabetic potential of Gongronema latifolium leaf fractionated compounds against proteins implicated in different molecular pathways related to the onset and progression of type 2 DM. A total of fifteen proteins that can act as type 2 DM therapeutic targets were identified from the literature and downloaded/modelled using respective repositories. After docking the compounds with the fifteen proteins, glycogen synthase kinase 3 beta (GSK 3β), glucagon-like peptide-1 receptor (GLP-1R) and human aldose reductase were chosen as the ideal targets due to their high binding affinities with the compounds. Subsequent in silico analysis like binding free energy, ADMET predictions using different servers, and machine-learning predictive models (QSAR) using kernel partial least square regression were employed to identify promising compounds against the three targets. The eleven identified compounds (Luteonin, Kampferol, Robinetin, Gallocatechin, Baicalin, Apigenin, Genistein, Rosmaric acid, Chicoric acid and Naringenin) formed stable complexes with the proteins, showed moderation for toxicity, drugability, GI absorptions and drug-drug interactions, though structure modifications may be needed for lead optimization. The predictive QSAR models with reliable correlation coefficient (R2) showed the potency of the compounds to act as inhibitors (pIC50) of aldose reductase and GSK 3β, and act as agonists (pEC50) of GLP-1R. Thus, this study experimental framework can be used to design compounds that can modulate proteins related to type 2 DM without inducing off-target effects.

Potential Role of Phytochemicals as Glucagon-like Peptide 1 Receptor (GLP-1R) Agonists in the Treatment of Diabetes Mellitus

“…The mechanisms of action of medicinal plants in diabetes management include the regeneration of β cells and the improvement of insulin secretion from the pancreas, increased glucose uptake by muscles and adipose tissue, decreased gluconeogenesis, and the inhibition of intestinal α-glucosidase [ 99 ]. Recent studies have identified GLP-1 modulatory activity in medicinal plants [ 100 , 101 , 102 ], which holds promise for diabetes management. Table 1 provides an overview of medicinal plants with GLP-1-inducing activity.…”

Assessing the Phytochemical Profile and Potential of Traditional Herbal Infusions against Aldose Reductase through In Silico Studies and LC-MS/MS Analysis

“…Based on the docking results, the infusion of O. majorana, another member of the Lamiaceae family, in which quercetin was detected [71], may also be an ideal candidate for the inhibition of AR [72]. In addition, caftaric acid, a phenolic acid of E. purpurea [73,74], exhibited important binding affinity toward AR [75], placing Echinacea among the herbs with possible action against hyperglycemia and metabolic syndrome induced by high blood sugar levels [76].…”

Profiling the Antidiabetic Potential of Compounds Identified from Fractionated Extracts of Entada africana toward Glucokinase Stimulation: Computational Insight

“…Computational modeling prediction of the ligand affinity for molecular targets in diabetes has been widely studied [23,24]. The inhibitory potential of compounds from the alliaceous plant protein tyrosine phosphatase 1B (PTP1B) has been predicted in silico as a possible mechanism of antidiabetic effects [25,26]. Glucokinase (GK) is an essential enzyme in glucose metabolism and a potential therapeutic target in type 2 diabetes [27].…”