The energy was defined as: Table 1 Binding energies of 20 derivative compounds with PTP1B and SHP-2 (kcal/mol). indicates the binding energy of ligand and PTP1B over SHP-2. The binding energies of the top 20 optimized candidates and NSC659447 with two proteins as well as E are listed in Table 1. Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 M. Its IC50 values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine the catalytic domains of PTP1B and SHP-2 by molecular dynamics (MD) simulations. . indicated that large numbers of PTP genes were encoded within the human genome, including trans-membrane, receptor-like, and intracellular, non receptor-like enzymes. PTPs have positive (signal-enhancing) or unfavorable (signal-attenuating) roles in a variety of Epirubicin normal transmission transductions . And PTPs have been shown to be unfavorable regulators of the insulin receptor. Inhibition of PTPs may be an effective method in the treatment of type 2 diabetes . Protein tyrosine phosphatase 1B (PTP1B), an intercellular non-receptor PTPs, is usually a key element in the unfavorable regulation of the insulin signaling pathway and a valid potential drug target Epirubicin for the treatment of type 2 diabetes and other associated metabolic syndromes [5,6]. It functions by dephosphorylation of specific phosphotyrosine (pTyr) residues around the insulin receptor and insulin receptor substrate proteins . Zinker reported that PTP1B antisense oligonucleotides (ASOs) could reduce PTP1B protein expression and could be used as potential therapeutics in the treatment of type 2 diabetes and obesity . Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2), another non-receptor PTP, has two Src homology 2 (SH2) domains and a catalytic domain name [9,10]. SHP-2 is considered to be a component of several intracellular transmission transduction systems involved in embryonic development that modulate cell division, differentiation, and migration, including that mediated by epidermal growth factors [3,10]. The identification of specific small-molecular-weight inhibitors IL1R2 antibody of tyrosine phosphatases is usually a challenging endeavor, because the base of the catalytic cleft, the signature motif, is usually highly conserved among all PTPs . Most advanced inhibitors of the tyrosine phosphatase PTP1B, could have some sort of effect on the closely related phosphatase SHP-2 with the same conversation owing to the homology in the targeting sites between PTP1B and SHP-2 . So the inhibitors of PTP1B could, at the same time, impact the activity of SHP-2. Therefore, undoubtedly, a large amount of inhibitors would be needed to acquire Epirubicin the comparable effect by the absence of SHP-2, which might lead to potential harmful and side effects. Troglitazone, a PTP1B inhibitor , which is a member of the thiazolidinedione (TZD) compounds, already has been forbidden to be used for the treatment of diabetes in clinical situations in recent years due to its side effects and toxicity [14,15]. Based on the structure and bioavailability of TZD compounds, the database of optimized structures was established on silicon. Therefore, the study of specific PTP1B inhibitors as drugs contributes to the increase of the specific affinity for PTP1B and prevents the combination with protein SHP-2 as far as possible. Pei tyrosine phosphatase assay is also shown below. The binding models of Compounds 13, 15 and 20 with PTP1B and SHP-2 are predicted and analyzed using a molecular dynamics (MD) simulation at the end of this Epirubicin article. The specific inhibitors of PTP1B in this article are not only considered as potential pre-drugs for treating diabetes and obesity but also as probers to discover the effect of PTP1B in the insulin signaling pathway. 2. Results and Discussion 2.1. Virtual Screening and Core-Hopping The database of drug-like structures from NCI  was screened by using Glide5 based on the conformation of the catalytic site of PTP1B. NSC659447, found to be the most potential lead compound for further modification, was divided into two parts, Ring-IZD (R-IZD) and Fragment-A (FA) as shown in Physique 2. In order to obtain specific inhibitors of PTP1B over SHP-2, the FA part was replaced by other segments of the fragment database to extend its length to site B. After optimization, the database of 20 candidates was established. Subsequently, each structure of the 20 candidates was redocked into the two receptors, PTP1B and SHP-2, respectively. Physique 2 lists the top 20 derivative candidates. Open in a separate window Physique 2 The top 20 derivative compounds offered by method of core-hopping. Ring-IZDs are colored in reddish; whereas Fragment-A is usually colored in black, which was replaced by package Core-Hopping. The candidates are.