Virtual and in vitro Screening Employing a Repurposing Approach Reveal 13-Cis-retinoic acid is a PTP1B Inhibitor.

Abstract

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options. A potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-gamma) and alpha-glucosidase. Some computational hits were then meticulously tested in vitro against PTP1B; particularly the 13-cis-retinoic acid ( 3a) showed an IC 50 of 0.044 mM and competitive inhibition. Molecular dynamics studies agrees that 3a can bind to the catalytic binding site of PTP1B. It is worth mentioning that 3a has been reported by the first time as an inhibitor of PTP1B in this work, making it a potentially valuable candidate for further studies in D2T treatment.