In silico analysis of highly disordered human IRS1 protein 3D structure to uncover new target for Metformin to ameliorate diabetes

Abstract

Abstract IRSs are cytoplasmic-skeleton proteins. It facilitates RTK signaling through insulin/IGF-1, insulin receptor, and Src-homology-2-domains. IRS1 is a cytoplasmic adaptor protein that helps in cellular growth, glucose metabolism, proliferation, and differentiation. IRS1 is a disordered protein with a hard-to-predict active site. Here we used the ab-initiomodeling tool I-Tasser and Discovery studio/DogSite server to model and determine the active site of IRS1 human protein (mol. wt. 131590.97Da) respectively. Newly designed protein model submitted with PMDB Id–PM0082210. GRAVY index of IRS1 (-0.675) indicated surface protein-water interaction. Protparam tool instability index (75.22) demonstrated disorderedness combined with loops owing to prolines/glycines. After refinement Ramachandran plot showed that 88 percent of AAs were present in the allowed region. Novel mode protein has beta-sheet, loops, and beta-hairpin but fewer helixes. Overall IRS1 has 10-α-helices, 22-β-sheets, 20-β-hairpins, 5-β-bulges, 47-strands, 105-β-turns and 8-γ-turns. Docking studies suggest that MH binds with the novel active site of IRS1 to increase insulin signaling to target and cure the T2DM target molecule. MD-simulations have been done to reveal the protein–ligand complex stability and robustness. The discovered MH’s target site to cure T2DM, a worldwide problem could be further authenticated by in vitro and in vivo experiments to determine the efficiency of metformin hydrochloride to cure this worldwide disease.