Exploration of Novel Sulpho Tyrosine Based Unnatural Amino Acid Ligand for Inhibition of Human Shp2; A Computational Approach

Abstract

The SHP2 protein is a Protein tyrosine phosphates (PTPs) protein family, it catalyze the dephosphorylation of phosphotyrosine residues in protein substrates and play a critical roles in regulating intracellular signal transduction and is responsible for controlling cell growth, differentiation, motility, and metabolism. Whereas, Shp2 has non-receptor PTP containing two N-terminal Src homology 2 (SH2) domains, a PTP domain, and a C-terminal tail. The SHP2 adopts an autoinhibited conformation in its basal state, whereby the N-terminal SH2 domain interacts with the PTP domain and blocks access to the catalytic site. The phosphorylated proteins bind to the SH2 domains of SHP2 and activate the dephosphorylation, which imparts down regulation of RTK-dependent signaling leads to activate oncogenes. Hence, The Shp2-PTPs interaction in physiological processes and that modulation of their enzymatic activity may constitute a therapeutic approach for the treatment of cancer. In the present work we have designed the four sulpho tyrosine based unnatural amino acid libraries through the Insilico modeling, to demonstrate the utility of, Phenyl sulfoaceticacid (PSAA) based Cap-group (a novel sulpho-Tyrosine Mimic) incorporated with novel N-heterocyclic based unnatural amino acid as a Spacer in Library-1, n-Dioxothiazolidene spacer in Library-2, n-pyridazine spacer in library-3 and n-imidazole spacer in library-4 respectively, which was development for novel anti cancerous Shp2-inhibitors, resulted in the five most potential ligand such as Ligand-1a &1b, 2a, 4a & 4b has shown to significant anti-cancerous shp2 inhibitor activity when compared with standard ligand SHP099.