Suppressor of Cytokine Signalling-3 as a Drug Target for Type 2 Diabetes Mellitus: A Structure-Guided Approach

The present study treats Suppressor of cytokine signalling 3 (SOCS-3) as a novel target for type 2 diabetes mellitus (T2DM) drug discovery. An in silico 3D structural evaluation and validation of the SOCS-3 and its cognate receptor, Insulin Receptor Beta (IR-B) was carried out. The active site of SOCS-3 was identified using computational tools and Protein-Protein docking with IR-B. The docking study with T2DM drugs and corroborating with the results of virtual screening using small molecules, ratify the residues of the catalytic site of SOCS-3, i.e. Arg-71 along with Asp-72, Ser-73, Ser-74, and Asp-92, to facilitate the binding. The T2DM drugs which belong to Sulfonylureas class show partial affinity towards SOCS-3. The ligands show acceptable pharmacokinetic properties in terms of Lipinski's rule of 5, Jorgensen's rule of 3, brain/blood partition coefficient, binding to human serum albumin and skin permeability. The identified ligands show good predicted IC50 values and hence can act as SOCS-3 antagonists. The structural data of SOCS-3 active site and the identified ligands are useful in development of new T2DM therapeutics.