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. 2022 Jun 24;23(13):7034.
doi: 10.3390/ijms23137034.

Synthesis, In Vitro, and Computational Studies of PTP1B Phosphatase Inhibitors Based on Oxovanadium(IV) and Dioxovanadium(V) Complexes

Tomasz Kostrzewa  1 , Jakub Jończyk  2 , Joanna Drzeżdżon  3 , Dagmara Jacewicz  3 , Magdalena Górska-Ponikowska  1   4   5 , Marcin Kołaczkowski  2 , Alicja Kuban-Jankowska  1
Affiliations

Synthesis, In Vitro, and Computational Studies of PTP1B Phosphatase Inhibitors Based on Oxovanadium(IV) and Dioxovanadium(V) Complexes

Tomasz Kostrzewa et al. Int J Mol Sci. .

Abstract

One of the main goals of recent bioinorganic chemistry studies has been to design and synthesize novel substances to treat human diseases. The promising compounds are metal-based and metal ion binding components such as vanadium-based compounds. The potential anticancer action of vanadium-based compounds is one of area of investigation in this field. In this study, we present five oxovanadium(IV) and dioxovanadium(V) complexes as potential PTP1B inhibitors with anticancer activity against the MCF-7 breast cancer cell line, the triple negative MDA-MB-231 breast cancer cell line, and the human keratinocyte HaCaT cell line. We observed that all tested compounds were effective inhibitors of PTP1B, which correlates with anticancer activity. [VO(dipic)(dmbipy)]·2 H2O (Compound 4) and [VOO(dipic)](2-phepyH)·H2O (Compound 5) possessed the greatest inhibitory effect, with IC50 185.4 ± 9.8 and 167.2 ± 8.0 nM, respectively. To obtain a better understanding of the relationship between the structure of the examined compounds and their activity, we performed a computer simulation of their binding inside the active site of PTP1B. We observed a stronger binding of complexes containing dipicolinic acid with PTP1B. Based on our simulations, we suggested that the studied complexes exert their activity by stabilizing the WPD-loop in an open position and limiting access to the P-loop.

Keywords: dioxovanadium(V) complexes; oxovanadium(IV) complexes; protein tyrosine phosphatase PTP1B; triple negative breast cancer.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyzes, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Molecular formulas of (1) [VO(dipic)(H2O)2]·2 H2O, (2) [VO(dipic)(bipy)]·H2O, (3) [VO(ida)(bipy)]·2 H2O, (4) [VO(dipic)(dmbipy)]·2 H2O, (5) [VOO(dipic)](2-phepyH)·H2O.
Figure 2
Figure 2
Enzymatic activity of PTP1B after treatment with different concentrations of Compounds 1–5 (a–e), sodium orthovanadate, as a standard inhibitor of PTP1B (f), and ligands present in the coordination sphere of the studied vanadium(IV,V) complexes (dipic, bipy, ida, dmbipy, 2-phephy) (g). The results are presented as a percentage of the control as means ± SD (n = 3, * p < 0.0001; ** p < 0.001; *** p < 0.01).
Figure 3
Figure 3
(a) Surface representation of PTP1B (PDB: 1ONZ) with color-coded active site loops. (b) Comparison of WPD-loop conformation observed in 1Q6T complex (closed position) and 1ONZ (open position).
Figure 4
Figure 4
Docking result of Compound 1 to the PTP1B active site (PDB: 1ONZ). Left panel presents a studied compound as white sticks with protein represented by a gray cartoon. Significant loops are highlighted with separate colors; P-loop in orange, WPD-loop in yellow, E-loop in green, and Q-loop in red. The most important amino acids are represented as sticks with the same color code. Coordinate bonds are marked with thin dotted lines. Hydrogen bonds are marked in magenta, ionic interaction in red, aromatic π-π or CH-π in green. Right panel presents 2D ligand interaction diagram.
Figure 5
Figure 5
Docking result of Compound 2 to the PTP1B active site (PDB: 1ONZ). Left panel presents a studied compound as white sticks with protein represented by a gray cartoon. Significant loops are highlighted with separate colors; P-loop in orange, WPD-loop in yellow, E-loop in green, and Q-loop in red. The most important amino acids are represented as sticks with the same color code. Coordinate bonds are marked with thin dotted lines. Hydrogen bonds are marked in magenta, ionic interaction in red, aromatic π-π or CH-π in green. Right panel presents 2D ligand interaction diagram.
Figure 6
Figure 6
Docking result of Compound 3 to the PTP1B active site (PDB: 1ONZ). Left panel presents a studied compound as white sticks with protein represented by a gray cartoon. Significant loops are highlighted with separate colors; P-loop in orange, WPD-loop in yellow, E-loop in green, and Q-loop in red. The most important amino acids are represented as sticks with the same color code. Coordinate bonds are marked with thin dotted lines. Hydrogen bonds are marked in magenta, ionic interaction in red, aromatic π-π, CH-π and cation-π in green. Right panel presents 2D ligand interaction diagram.
Figure 7
Figure 7
Docking result of Compound 4 to the PTP1B active site (PDB: 1ONZ). Left panel presents a studied compound as white sticks with protein represented by a gray cartoon. Significant loops are highlighted with separate colors; P-loop in orange, WPD-loop in yellow, E-loop in green, and Q-loop in red. The most important amino acids are represented as sticks with the same color code. Coordinate bonds are marked with thin dotted lines. Hydrogen bonds are marked in magenta, ionic interaction in red, aromatic π-π, CH-π and cation-π in green. Right panel presents 2D ligand interaction diagram.
Figure 8
Figure 8
Result of MD simulation of Compound 4 (white sticks) and the PTP1B complex (1ONZ). Transparent structures presents a studied complex on start of simulation and filled structures present position after 50 ns. Significant loops are highlighted with separate colors; P-loop in orange, WPD-loop in yellow, E-loop in green, and Q-loop in red.
Figure 9
Figure 9
The above plot shows the RMSD evolution of a protein backbone (green) and Compound 4 (aligned to its reference conformation – pink, aligned on the protein backbone of the reference position - magenta) calculated for all frames in the simulation.
Figure 10
Figure 10
Result of MD simulation of Compound 4 (white sticks) and the PTP1B complex (2FJN). Transparent structures present a studied complex on start of simulation and filled structures present position after 50 ns. We highlight significant loops with separate colors; P-loop in orange, WPD-loop in yellow, E-loop in green, and Q-loop in red.
Figure 11
Figure 11
The above plot shows the RMSD evolution of a protein backbone (green) and ligand 4 aligned with the protein backbone of the reference position - magenta calculated for all frames in the simulation.
Figure 12
Figure 12
Changes in binding free energy for Compound 4 during MD simulation measured at 5 ns intervals.
Figure 13
Figure 13
Cytotoxicity of Compounds 1–5 and sodium orthovanadate at concentrations 25, 50, and 100 µM against (a) the breast cancer MCF-7 cell line; (b) the breast cancer MDA-MB-231 cell line; (c) the human keratinocyte HaCaT cell line. Cell viability was measured by the MTT cell viability assay. The results were presented as a percentage of the control (mean ± SD, n = 3, * p < 0.0001; ** p < 0.001; **** p < 0.1).
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