Structural insights into suppressor of cytokine signaling 1 protein‐ identification of new leads for type 2 diabetes mellitus

Abstract

The study considers the Suppressor of cytokine signaling 1 (SOCS1) protein as a novel Type 2 diabetes mellitus (T2DM) drug target. T2DM in human beings is also triggered by the over expression of SOCS proteins. The SOCS1 acts as a ubiquitin ligase (E3), degrades Insulin Receptor Substrate 1 and 2 (IRS1 and IRS2) proteins, and causes insulin resistance. Therefore, the structure of the SOCS1 protein was evaluated using homology-modeling and molecular dynamics methods and validated using standard computational protocols. The Protein-Protein docking study of SOCS1 with its natural substrates, IRS1 and IRS2, and subsequent solvent accessible surface area analysis gave insight into the binding region of the SOCS1 protein. The in silico active site prediction tools highlight the residues Val155 to Ile211 in SOCS1 being implicated in the ubiquitin mediated protein degradation of the proteins IRS1 and IRS2. Virtual screening in the active site region, using large structural databases, results in selective lead structures with 3-Pyridinol, Xanthine, and Alanine moieties as Pharmacophore. The virtual screening study shows that the residues Glu149, Gly187, Arg188, Leu191, and Ser205 of the SOCS1 are important for binding. The docking study with current anti-diabetic therapeutics shows that the drugs Glibenclamide and Glyclopyramide have a partial affinity towards SOCS1. The predicted ADMET and IC properties for the identified ligands are within the acceptable range with drug-like properties. The structural data of SOCS1, its active site, and the identified lead structures are expedient in the development of new T2DM therapeutics.

Effect of (−)-Epigallocatechin Gallate on Activation of JAK/STAT Signaling Pathway by Staphylococcal Enterotoxin A

“…The development of Type II diabetes in humans is associated with excessive weight and obesity and is caused by overexpression of the SOCS protein [ 6 ]. Type II diabetics carry a high risk of S. aureus colonization and overt infections.…”

“…In adipocytes and hepatocytes, interleukin 6 (IL-6) binds to gp130 and induces suppressor of cytokine-signaling 1 (SOCS1) expression via the JAK/STAT pathway. This inhibits tyrosine phosphorylation, thereby inhibiting the action of insulin [ 5 , 6 ]. SOCS1 regulates both the adaptive and the innate immune responses [ 7 ].…”

Latent M. tuberculosis infection is associated with increased inflammatory cytokine and decreased suppressor of cytokine signalling (SOCS)‐3 in the diabetic host

“…51 Further, SOCS1 has been shown to inhibit insulin receptor substrate (IRS) proteins leading to insulin resistance. 52 Upregulated SOCS1 in response to mycobacterial antigen stimulation in DM may be associated with increased insulin resistance in this group.…”

Downregulation of microRNA‑126 is inversely correlated with insulin receptor substrate‑1 protein expression in colorectal cancer and is associated with advanced stages of disease

“…IRS-1, a member of the IRS family, is the principle substrate of the insulin-like growth factor I receptor and the insulin receptor, and plays an essential role in cytokine signaling ( 25 ). IRS-1 mediates a range of biological responses, including apoptosis and cell differentiation, by binding to and activating enzymes or adapter molecules ( 26 , 27 ).…”