Virtual and in Vitro Screening Employing a Repurposing Approach Reveal 13-cis-Retinoic Acid is a PTP1B Inhibitor.

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, as approved drugs targeting different pharmacological objectives are still unavailable. One 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-γ) and α-glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13-cis-retinoic acid (3a) showing an IC50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment.

UHPLC-MS/MS Studies and Antiproliferative Effects in Breast Cancer Cells of Mexican Sargassum.

BACKGROUND: Sargassum is a marine organism that, under specific conditions, drastically increases its population damaging the environment and risking other organisms. However, sargassum could represent a source of bioactive compounds to treat different diseases such as cancer. Thus, aqueous, ethanolic, and ethyl acetate extracts of sargassum from Playa del Carmen, Mexico, were subjected to metabolomic and antiproliferative assays in breast cancer cells. OBJECTIVE: To evaluate the biological effect of different extracts of sargassum, its toxicity over Artemia salina and its antiproliferative effect tested in MCF-7, MDA-MB-231, and NIH3T3 cell lines. Finally, using UHPLC-MS/MS to identify the metabolites in each extract to correlate them with its antiproliferative effect. METHODS: The sargassum sample collection was carried out in September at three different points in Playa del Carmen, Quintana Roo, Mexico. The aqueous, ethanolic, and ethyl acetate extracts of Mexican sargassum were obtained by evaporation of solvent and lyophilization. Then, these extracts were evaluated in the cytotoxicity bioassay of Artemia salina. Next, its antiproliferative effect was assessed in MCF-7, MDA-MB-231, and NIH3T3 cell lines. Using UHPLC-MS/MS, the metabolites present in each extract were identified. Finally, docking studies on sphingosine kinase 1 (PDB ID: 3VZB) of sphingosine were carried out. RESULTS: The extracts from sargassum showed a greater effect in the antiproliferative assays in cells than in cytotoxic assays in Artemia salina. The ethanolic extract obtained from sargassum showed the best antiproliferative activity in MCF7 and MDA-MB-231 cells. Despite its antiproliferative effect on NIH3T3 cells, an additional extract is required indicating that this extract has compounds that could have a better effect on cancer cells in fibroblast (NIH3T3). The UHPLC-MS/MS of ethanolic and the ethyl acetate extract showed that these extracts have compounds such as sphinganine C16, N, N-Dimethylsphingosine compound, and that it could be possible that the effect observed is due to their metabolites which could be ligands for the sphingosine kinase 1 as demonstrated by docking studies. CONCLUSION: The ethanolic extract obtained from sargassum has better antiproliferative activity, despite not having a cytotoxic effect in Artemia salina. The antiproliferative effect could be related to the sphinganine C16, N,NDimethylphingosine identified with more abundance by UHPLC-MS/MS. In addition, these metabolites could be targets of sphingosine kinase 1.