The Discovery of a Novel and Selective Inhibitor of PTP1B Over TCPTP: 3D QSAR Pharmacophore Modeling, Virtual Screening, Synthesis, and Biological Evaluation

Abstract

Given the special role of insulin and leptin signaling in various biological responses, protein-tyrosine phosphatase-1B (PTP1B) was regarded as a novel therapeutic target for treating type 2 diabetes and obesity. However, owing to the highly conserved (sequence identity of about 74%) in active pocket, targeting PTP1B for drug discovery is a great challenge. In this study, we employed the software package Discovery Studio to develop 3D QSAR pharmacophore models for PTP1B and TCPTP inhibitors. It was further validated by three methods (cost analysis, test set prediction, and Fisher's test) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective PTP1B inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective inhibitor of PTP1B over TCPTP. After that, a most likely binding mode was proposed. Thus, the findings reported here may provide a new strategy in discovering selective PTP1B inhibitors.

Combined Ligand‐ and Receptor‐Based Virtual Screening Methodology to Identify Structurally Diverse Protein Tyrosine Phosphatase 1B Inhibitors

“…To our knowledge, these compounds represent the highest inhibitory potency for PTP1B obtained by any VS method. Moreover, although previous VS protocols have also obtained PTP1B inhibitors with activity values in the low μ m range, they were similar in structure. For example, Ma et al .…”

“…VS workflows capable of further exploring the chemical space by identifying new chemical entities with diverse structures may prove useful in the pursuit of molecules that show potential for use as new lead compounds for the design of PTP1B inhibitors with a good balance between potency and bioavailability. To date, several VS workflows have been developed for the purpose of discovering novel PTP1B inhibitors . Despite their success in identifying PTP1B inhibitors, they often present drawbacks such as few or no compounds tested in vitro, low percentages of active compounds and relatively low activity values of the identified inhibitors (see Table ).…”

Identification of hit compounds for squalene synthase: Three‐dimensional quantitative structure‐activity relationship pharmacophore modeling, virtual screening, molecular docking, binding free energy calculation, and molecular dynamic simulation

“…Three‐dimensional quantitative structure‐activity relationship pharmacophore models were generated by 3D‐QSAR pharmacophore generation protocol implemented in DS 3.1. Before the generation of pharmacophore models, uncertain values were set to 2 representing the ratio of the uncertainty range of measured SAR pharmacophore generation module, excluded volumes were set to 3, and pharmacophore features were selected as the same with the features in Hip‐Hop pharmacophore model. All the rest 3D‐QSAR pharmacophore generation parameters were kept at their default values.…”

Type 2 Diabetes Mellitus and Protein-Tyrosine Phosphatase 1B1

“…In addition, various other classes of compounds have been reported to have PTP1B inhibitory potential. Including isothiazolinones [41], paracaseolide A analogs [42], phosphotyrosine mimetic [43], terpenoids [44] and many more groups that show PTP1B inhibitory activity [45,46]. Natural molecules as PTP1B inhibitor and therapy of Type 2 diabetes: Creatures of nature synthesized a variety of novel structure and secondary metabolites during biological evolution.…”