In Vitro and In Silico Analysis of PTP1B Inhibitors from Cleistocalyx operculatus Leaves and Their Effect on Glucose Uptake
Abstract
:1. Introduction
2. Materials and Methods
2.1. General Experimental Procedures
2.2. Plant Material
2.3. Extraction and Isolation
2.4. Spectroscopic and Physical Characteristic of Compounds
2.5. In Vitro PTP1B Inhibition Assay
2.6. Kinetic Analysis with PTP1B
2.7. Cell Culture and Differentiation of 3T3-L1 Adipocytes
2.8. Measurement of Glucose Uptake Using the 2-NBDG Probe
2.9. Molecular Docking Studies on the PTP1B Enzyme
2.10. Statistical Analysis
3. Results
3.1. Structure Elucidation of Compounds 1−3 from Cleistocalyx Operculatus
3.2. PTP1B Inhibitory Activity of Compounds 1−17 and Enzyme Kinetics
3.3. Structure Activity Relationship (SAR) Analysis and Molecular Docking Experiments
3.4. Effect of Stimulating Glucose Uptake in Adipocytes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Position | 1 | 2 | 3 | |||
---|---|---|---|---|---|---|
δH (J in Hz) | δC | δH (J in Hz) | δC | δH (J in Hz) | δC | |
1 | 1.73 d (13.1) 0.99 m | 39.8 | 1.75 m 1.08 m | 39.6 | 2.62 dd (12.7, 5.0) 1.72 m | 48.2 |
2 | 1.86 m 1.80 m | 28.8 | 1.92 m 1.86 m | 28.3 | 4.13 m | 73.7 |
3 | 3.27 dd, (11.3, 4.7) | 78.3 | 4.05 dd (11.3, 4.0) | 74.0 | 4.38 d (8.8) | 79.9 |
4 | 39.9 | 43.3 | 151.9 | |||
5 | 0.88 m | 56.5 | 1.54 m | 49.6 | 5.04 br d (12.2) | 50.4 |
6 | 1.62 m 1.42 m | 19.3 | 1.68 m 1.45 m | 19.2 | 1.64 m 1.50 m | 21.1 |
7 | 3.01 m 1.93 m | 38.8 | 2.15 m 1.87 m | 38.6 | 1.28 m 1.06 m | 30.5 |
8 | 41.3 | 41.3 | 42.3 | |||
9 | 1.93 m | 52.2 | 2.03 m | 52.2 | 1.90 br s | 50.1 |
10 | 38.3 | 38.2 | 38.7 | |||
11 | 1.57 m 1.31 m | 21.7 | 1.60 m 1.35 m | 21.7 | 3.32 dd (3.1, 2.4) | 55.3 |
12 | 2.79 m 1.89 m | 28.1 | 2.70 m 2.01 m | 27.4 | 3.07 d (3.7) | 56.8 |
13 | 2.79 m | 40.7 | 2.71 m | 40.7 | 89.7 | |
14 | 60.3 | 60.4 | 42.2 | |||
15 | 2.50 d (13.4) 1.57 m | 29.1 | 2.47 d (13.4) 1.56 m | 29.0 | 1.73 m 1.03 m | 27.5 |
16 | 2.68 m 1.93 m | 35.3 | 2.65 m 1.88 m | 35.4 | 2.31 m 1.42 m | 23.5 |
17 | 57.3 | 57.3 | 45.7 | |||
18 | 2.33 t (11.1) | 53.0 | 2.13 m | 52.9 | 1.88 m | 61.6 |
19 | 3.53 td (11.3, 4.7) | 44.2 | 3.51 td (10.9, 4.2) | 48.2 | 2.71 m | 36.6 |
20 | 156.5 | 151.2 | 152.4 | |||
21 | 2.20 m 1.63 m | 33.0 | 2.03 m 1.46 m | 31.3 | 2.23 m 2.29 m | 32.4 |
22 | 2.01 m 1.57 m | 37.5 | 2.02 m 1.45 m | 37.7 | 1.96 dt (12.9, 3.1) 1.62 m | 33.8 |
23 | 1.08 s | 29.0 | 4.10 d (10.3) 3.59 d (10.3) | 68.5 | 5.89 br s 4.99 br s | 105.7 |
24 | 1.01 s | 17.0 | 1.06 s | 13.5 | ||
25 | 0.91 s | 17.5 | 0.99 s | 17.8 | 0.91 s | 16.3 |
26 | 1.18 s | 17.9 | 1.20 s | 17.9 | 1.17 s | 20.7 |
27 | 178.8 | 178.8 | 1.18 s | 16.7 | ||
28 | 177.3 | 177.4 | 178.6 | |||
29 | 5.61 br s 5.38 br s | 107.3 | 5.04 br s 4.81 br s | 111.0 | 1.45 d (6.3) | 16.9 |
30 | 4.73 d (15.0) 4.56 d (15.0) | 64.7 | 1.89 s | 19.7 | 4.87 br s 4.81 br s | 108.7 |
OCH3 | 3.77 s | 51.9 | 3.77 s | 52.0 |
Compounds | IC50 (μM) | Inhibition Type b | Ki (μM) c |
---|---|---|---|
1 | >20 | - | - |
2 | >20 | - | - |
3 | >20 | - | - |
4 | 8.7 ± 0.6 | - | - |
5 | 2.2 ± 0.1 | - | - |
6 | 4.1 ± 0.2 | Non-competitive | 2.8 ± 0.4 |
7 | >20 | - | - |
8 | >20 | - | - |
9 | 4.4 ± 0.5 | Non-competitive | 7.6 ± 1.2 |
10 | 12.2 ± 0.3 | - | - |
11 | 14.1 ± 0.3 | - | - |
12 | 1.7 ± 0.8 | - | - |
13 | 1.28 ± 0.1 | Non-competitive | 3.2 ± 0.6 |
14 | 3.6 ± 0.2 | - | - |
15 | 6.6 ± 0.6 | - | - |
16 | 3.6 ± 0.4 | - | - |
17 | 2.6 ± 0.3 | Non-competitive | 2.7 ± 0.4 |
Ursolic acid d | 2.9 ± 0.2 µM | - | - |
Libdock Score | Hydrogen Bond | Hydrophobic | Other Interactions | ||||
---|---|---|---|---|---|---|---|
π-π Stacked | π-σ | π-Alkyl | π Anion/Cation | π-Sulfur | |||
6 | 96.83 | Ala189 Glu200 | Phe280 | Lys197 Leu192 Phe196 | |||
9 | 81.57 | Asn193 Lys197 Glu276 | Ala189 Phe280 | ||||
13 | 104.44 | Lys197 | Phe 280 | Ala189 Leu192 | |||
17 | 106.92 | Lys197 Lys279 | Phe280 | Ala189 Leu192 | |||
Docking control (PDB:1T4J ligand) | 148.67 | Asn193 Lys197 Phe280 | Phe280 | Ala189 Leu192 Phe196 | Phe280 | Met182 |
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Ponce-Zea, J.-E.; Ryu, B.; Lee, J.-Y.; Park, E.-J.; Mai, V.-H.; Doan, T.-P.; Lee, H.-J.; Oh, W.-K. In Vitro and In Silico Analysis of PTP1B Inhibitors from Cleistocalyx operculatus Leaves and Their Effect on Glucose Uptake. Nutrients 2024, 16, 2839. https://doi.org/10.3390/nu16172839
Ponce-Zea J-E, Ryu B, Lee J-Y, Park E-J, Mai V-H, Doan T-P, Lee H-J, Oh W-K. In Vitro and In Silico Analysis of PTP1B Inhibitors from Cleistocalyx operculatus Leaves and Their Effect on Glucose Uptake. Nutrients. 2024; 16(17):2839. https://doi.org/10.3390/nu16172839
Chicago/Turabian StylePonce-Zea, Jorge-Eduardo, Byeol Ryu, Ju-Yong Lee, Eun-Jin Park, Van-Hieu Mai, Thi-Phuong Doan, Hee-Ju Lee, and Won-Keun Oh. 2024. "In Vitro and In Silico Analysis of PTP1B Inhibitors from Cleistocalyx operculatus Leaves and Their Effect on Glucose Uptake" Nutrients 16, no. 17: 2839. https://doi.org/10.3390/nu16172839