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Updated: Jun 4, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Virtual and in Vitro Screening Employing a Repurposing Approach Reveal 13-cis-Retinoic Acid is a PTP1B Inhibitor
Reyna Del Carmen Navarrete-Mondragón1, Francisco Cortés-Benítez2, Jessica Elena Mendieta-Wejebe3
1Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana [1, Ciudad de México, 04960, México.
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, 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.
Insights
Researchers identified 13-cis-retinoic acid as a novel inhibitor of protein tyrosine phosphatase 1B (PTP1B), a key target for type 2 diabetes (T2D) treatment. This finding offers a promising new avenue for developing effective T2D therapies.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Current type 2 diabetes (T2D) treatments, including lifestyle changes and medications, aim to improve insulin function but have limitations.
- There is a critical need for novel therapeutic strategies targeting different biological pathways in T2D management.
- Protein tyrosine phosphatase 1B (PTP1B) is a significant negative regulator of insulin signaling, making it a promising therapeutic target.
Purpose of the Study:
- To computationally screen existing and investigational drugs for potential PTP1B inhibitory activity.
- To identify novel PTP1B inhibitors using a drug repurposing approach.
- To evaluate the efficacy and mechanism of action of identified PTP1B inhibitors.
Main Methods:
- Utilized cheminformatics and molecular docking for comprehensive computational screening of drugs targeting PPAR-γ and α-glucosidase.
- Conducted in vitro assays to test the inhibitory potential of computational hits against PTP1B.
- Performed molecular dynamics simulations to confirm binding interactions of the lead compound with PTP1B.
Main Results:
- Identified 13-cis-retinoic acid (3a) as a potent PTP1B inhibitor with an IC50 of 0.044 µM.
- Demonstrated that 3a exhibits competitive inhibition kinetics.
- Confirmed through molecular dynamics that 3a binds to the catalytic site of PTP1B.
Conclusions:
- 13-cis-retinoic acid is reported for the first time as a PTP1B inhibitor.
- 3a represents a promising candidate for further investigation in the development of new type 2 diabetes treatments.
- This study highlights the potential of drug repurposing for identifying novel therapeutic agents for T2D.
