In silico insights into natural ligands affecting key proteins in the insulin signaling pathway: AS160 and PTEN.رسالة ماجستير

Abstract

Insulin is a crucial hormone that regulates blood sugar levels. It is secreted post-prandial and binds to insulin receptors in liver, muscle, and fat cells. This leads to uptake of glucose in the form of glycogen or fat, a process that involves multiple proteins and enzymes, including PTEN and AS160, which are regulatory proteins in the insulin pathway and inhibit the insulin cascade. Deficits in the insulin signal pathway lead to insulin resistance and, eventually, type 2 diabetes mellitus. In natural compounds extracted from plant species, such as D-talose, inositol, glucopyranose, and alpha-linolenic acid, have been reported as anti-diabetic agents. This in silico study reports potential natural chemical inhibitors for two main protein inhibitors in the insulin signaling pathway, PTEN and AS160, and as such potential treatment of diabetes mellitus. Therefore, we aim to predict the drug-likeness potential of 17 natural phytochemicals from Gundelia tournefortii and Ocimum to treat diabetes. This is achieved by testing their interaction (the maximum binding affinity and the interacting amino acid residues) with AS160 and PTEN in silico, using Autodock tools. Then we identified their drug-likeness and ADME (absorption, distribution, metabolism and excretion) properties using swissADME web tool where all the selected ligands were screened based on the Lipinski’s rule of five to find the drug likeness and other properties using the Bioavailability Radar. Several compounds have shown high binding affinities with both target protein e.g., beta-sitosterol, beta-amyrin, lupeol-trifluoroacetate, lupeol and Stigmasterol. For ADME analysis, the study analyzed 17 compounds, following Lipinski's rule of five, with the best bioavailability found in stearic-acid, palmitic-acid, ferulic-acid, isovanillic-acid, 4-methoxybenzoic-acid, and 4-hydroxybenzoic-acid. However, 3,4-dihydroxybenzoic-acid bioactive compounds show good solubility but not specificity; they react nonspecifically with numerous biological targets rather VI than specifically affecting one desired target- and an inhibitor of Cytochromes P450 (CYP enzymes). Beta-sitosterol, beta-Amyrin, and lupeol-trifluoroacetate show poor solubility and no excretion problems. The results indicated that five out of 17 tested ligands bind well with both target proteins; PTEN and AS160 based on their high binding affinity. Taking this together, besides their drug-likeness properties, they can be potent antidiabetic drugs to be tested in vitro and in vivo systems.