Virtual Screening Based Discovery of PTP1B Inhibitors and Their Biological Evaluations

Abstract

Background : The discovery of novel antidiabetics for the treatment of type 2 diabetes mellitus (T2DM) is an important task nowadays because the current treatment approaches have certain limitations. The reported studies showed that the protein tyrosine phosphatase 1B (PTP1B) is a valuable target, can be used to develop significant antidiabetic molecules. Objective: In the present investigation, computational methods and biological evaluation studies have been applied to develop novel PTP1B inhibitors with good enzyme binding affinity and activity. Methods: Virtual screening (docking) analysis of SPECS database compounds on PTP1B enzyme was performed using Schrodinger software. In vitro and in vivo biological evaluations had been conducted with the identified hits. Results: The results revealed that the molecules identified through these studies have shown significant interactions with the active site residues of the PTP1B enzyme. The compounds S1 and S2 provided significant binding interactions with the residues (Arg221 and Gln262) and have shown considerable in vitro PTP1B inhibitory activity and in vivo antidiabetic activity. The compounds S1 and S2 possessed 35.44±0.12% and 33.68±0.08% inhibitory activities, respectively. Conclusion: These identified hits will be used as a template for design and development of novel PTP1B inhibitors with a compatible pharmacokinetic profile.