Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine phosphatase 1B (PTP1B) is a highly validated target for the treatment of type 2 diabetes and obesity. Previous studies have shown that bromophenols from marine red alga Rhodomela confervoides can inhibit PTP1B activity. However, traditional in vitro enzymatic assays may result in false positive activity. Here, we reported a successful application of molecular docking and surface plasmon resonance (SPR) assay for the characterization of small-molecule PTP1B inhibitors with high affinity. First, molecular docking study indicated that six bromophenol compounds preferred to bind PTP1B with open conformation rather than one with closed conformation. Next, SPR study indicated that compound 3 was the most potent and stable PTP1B inhibitor at the nanomolar level. Then Lineweaver-Burk plot data showed that compound 3 was a competitive PTP1B inhibitor. Moreover, compound 3 could improve palmitate-induced insulin resistance in HepG2 cells. Taken together, molecular docking and SPR-based methodology could apply in the development of PTP1B inhibitors with high affinity.
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PMID:Binding properties of marine bromophenols with human protein tyrosine phosphatase 1B: Molecular docking, surface plasmon resonance and cellular insulin resistance study. 3261 61

Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of diabetes and obesity. Ertiprotafib is a PTP1B inhibitor that reached the clinical trial stage for the treatment of diabetes. Interestingly, Ertiprotafib reduces the melting temperature of PTP1B in differential scanning fluorimetry (DSF) assays, different from most drugs that increase the stability of their target upon binding. No molecular data on how Ertiprotafib functions has been published. Thus, to gain molecular insights into the mode of action of Ertiprotafib, we used biomolecular NMR spectroscopy to characterize the molecular details of the PTP1B:Ertiprotafib interaction. Our results show that Ertiprotafib induces aggregation of PTP1B in a concentration dependent manner. This shows that the insufficient clinical efficacy and adverse effects caused by Ertiprotafib is due to its tendency to cause aggregation of PTP1B.
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PMID:The mode of action of the Protein tyrosine phosphatase 1B inhibitor Ertiprotafib. 3300 22


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