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

• Published in: Journal of molecular recognition Vol. 31; no. 7; pp. e2706 - n/a
• Main Authors: Dumpati, Ramakrishna, Ramatenki, Vishwanath, Vadija, Rajender, Vellanki, Santhiprada, Vuruputuri, Uma
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2018
• Subjects: ADMET; Alanine; Binding; Computer applications; Cytokines; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Docking; Drug development; Glibenclamide; Homology; homology modelling; Insulin; Insulin receptor substrate 1; IRS1; IRS2; Molecular chains; Molecular dynamics; Pharmacology; Predictions; Protein structure; Proteins; protein‐protein docking; Residues; Screening; Signaling; SOCS-1 protein; SOCS1; Substrates; type 2 diabetes mellitus; Ubiquitin; Ubiquitin-protein ligase; virtual screening; homology modelling; SOCS1; virtual screening; IRS1; protein-protein docking; type 2 diabetes mellitus; IRS2; ADMET
• ISSN: 0952-3499; 1099-1352
• DOI: 10.1002/jmr.2706

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 IC50 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. The complete 3D structure of the SOCS1 protein was evaluated and validated using insilico techniques. Docking of SOCS1 with insulin receptor substrates 1 and 2 and SASA analysis shows that SOCS box domain of SOCS1 is involved in complex formation. Glu149, Gly187, Arg188, Leu191, and Ser205 of SOCS1 are crucial in binding with ligands and T2DM drugs. Identified leads have 3‐Pyridinol, Xanthine, and Alanine moieties as Pharmacophore. The predicted ADMET and IC50 values for the ligands are within the acceptable range.