Drug Discovery of Plausible Lead Natural Compounds That Target the Insulin Signaling Pathway: Bioinformatics Approaches

Abstract

The growing smooth talk in the field of natural compounds is due to the ancient and current interest in herbal medicine and their potentially positive effects on health. Dozens of antidiabetic natural compounds were reported and tested in vivo, in silico, and in vitro. The role of these natural compounds, their actions on the insulin signaling pathway, and the stimulation of the glucose transporter-4 (GLUT4) insulin-responsive translocation to the plasma membrane (PM) are all crucial in the treatment of diabetes and insulin resistance. In this review, we collected and summarized a group of available in vivo and in vitro studies which targeted isolated phytochemicals with possible antidiabetic activity. Moreover, the in silico docking of natural compounds with some of the insulin signaling cascade key proteins is also summarized based on the current literature. In this review, hundreds of recent studies on pure natural compounds that alleviate type II diabetes mellitus (type II DM) were revised. We focused on natural compounds that could potentially regulate blood glucose and stimulate GLUT4 translocation through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. On attempt to point out potential new natural antidiabetic compounds, this review also focuses on natural ingredients that were shown to interact with proteins in the insulin signaling pathway in silico, regardless of their in vitro/in vivo antidiabetic activity. We invite interested researchers to test these compounds as potential novel type II DM drugs and explore their therapeutic mechanisms.

In Vivo and In Vitro Antidiabetic Efficacy of Aqueous and Methanolic Extracts of Orthosiphon Stamineus Benth

“…4-aminobutanoic, also known as gamma-aminobutyric acid (GABA), improved insulin resistance in diabetic patients by increasing the expression of GLUT4 [ 26 ]. Quercetin increased expression of GLUT4 [ 5 ]. Caffeic acid and chlorogenic acid were reported to possess antidiabetic activity, yet their activity was not associated directly with GLUT4 activity.…”

“…PI3-K phosphorylates phosphatidylinositol-4, 5-bisphosphate (PIP2) to yield phosphatidylinositol-3, 4, 5-triphosphate (PIP3). PIP3 activates Akt (protein kinase B), which then phosphorylates many substrates, including Akt substrate of 160 kDa (AS160), leading to its inhibition and thus augmenting GLUT4-containing vesicle translocation and fusion with the plasma membrane (PM) [ 5 ]. GLUT4 translocation to the PM is also triggered by AMP-activated protein kinase (AMPK) under certain conditions such as muscle contraction, increased cellular [AMP]/[ATP] ratio and deprivation of glucose or oxygen.…”

“…GLUT4 translocation to the PM is also triggered by AMP-activated protein kinase (AMPK) under certain conditions such as muscle contraction, increased cellular [AMP]/[ATP] ratio and deprivation of glucose or oxygen. AMPK activation in skeletal muscle promotes GLUT4 trafficking to the PM and enhanced glucose uptake in the insulin independent pathway [ 4 , 5 ].…”

Tinosporaside from Tinospora cordifolia Encourages Skeletal Muscle Glucose Transport through Both PI-3-Kinase- and AMPK-Dependent Mechanisms

“…Activation of AMPK could recruit AS160, which further contributes to stimulation of GLUT4 translocation and the subsequent increase in the rate of glucose uptake in skeletal muscle [ 29 ]. Several naturally-occurring compounds like berberine [ 30 , 31 , 32 ], tangeretin [ 33 ], resveratol [ 34 ], and dietary phytoestrogens [ 35 ] have been reported to activate the AMPK pathway and improve the glucose and lipid homeostasis in in vivo models. Taken together, our findings provide adequate evidence for the idea that anti-hyperglycemic potential of tinosporaside is associated with enhanced glucose utilization in skeletal muscle, mediated through activation of both PI3K- and AMPK-dependent signaling pathways.…”

Hypoglycemic and antioxidant potency of ethyl acetate fraction of hydro-methanolic extract (60:40) of Tamarindus indica Linn. seed in streptozotocin-induced diabetic experimental animal

“…These are widely used worldwide indicating that plants are an evolving part of current and efficient technology dependent drugs. Products obtained naturally from plants are the main source for inventing leading candidates and it also plays significant role in the forthcoming drug development programme (Chukwuma et al, 2019;Jugran et al, 2021;Shanak et al, 2022) According to the World Health Organization (WHO), a total of 21,000 plants are used for medicinal purposes all around the globe. Out of these about 400 plants are suitable for the management of diabetes.…”