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Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Binding properties of marine bromophenols with human protein tyrosine phosphatase 1B: Molecular docking, surface
Jiao Luo1, Renshuai Zhang2, Xuehe Wang3
1School of Public Health, Qingdao University, Qingdao 266071, China; Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, 7 Nanhai Road, Qingdao 266071, China.
Abstract:
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.
Insights
Marine bromophenols show potential as Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors for diabetes and obesity. Compound 3, identified using molecular docking and SPR, effectively inhibits PTP1B and improves insulin resistance.
Area of Science:
- Biochemistry
- Pharmacology
- Marine Biotechnology
Background:
- Protein Tyrosine Phosphatase 1B (PTP1B) is a key therapeutic target for type 2 diabetes and obesity.
- Marine red alga Rhodomela confervoides yields bromophenols with reported PTP1B inhibitory activity.
- In vitro enzymatic assays can yield false positives, necessitating advanced characterization methods.
Purpose of the Study:
- To characterize high-affinity small-molecule PTP1B inhibitors using molecular docking and Surface Plasmon Resonance (SPR).
- To evaluate the inhibitory mechanism and cellular efficacy of bromophenols from Rhodomela confervoides.
Main Methods:
- Molecular docking simulations to predict binding modes of bromophenols to PTP1B.
- Surface Plasmon Resonance (SPR) assays to determine binding affinity and kinetics.
- Lineweaver-Burk plot analysis to elucidate the inhibition mechanism.
- Cell-based assays using HepG2 cells to assess the effect on insulin resistance.
Main Results:
- Molecular docking revealed preferred binding of six bromophenols to an open PTP1B conformation.
- SPR identified Compound 3 as a potent and stable PTP1B inhibitor with nanomolar affinity.
- Compound 3 acts as a competitive inhibitor of PTP1B.
- Compound 3 demonstrated efficacy in improving palmitate-induced insulin resistance in HepG2 cells.
Conclusions:
- A combined molecular docking and SPR approach effectively identifies high-affinity PTP1B inhibitors.
- Compound 3 is a promising PTP1B inhibitor with potential therapeutic applications for metabolic disorders.
- This methodology aids in the development of PTP1B inhibitors, overcoming limitations of traditional assays.
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