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. 2024 Jul 16;25(14):7787.
doi: 10.3390/ijms25147787.

Variations of VEGFR2 Chemical Space: Stimulator and Inhibitory Peptides

Claudiu N Lungu  1   2 , Ionel I Mangalagiu  2 , Gabriela Gurau  1   2 , Mihaela Cezarina Mehedinti  1   2
Affiliations

Variations of VEGFR2 Chemical Space: Stimulator and Inhibitory Peptides

Claudiu N Lungu et al. Int J Mol Sci. .

Abstract

The kinase pathway plays a crucial role in blood vessel function. Particular attention is paid to VEGFR type 2 angiogenesis and vascular morphogenesis as the tyrosine kinase pathway is preferentially activated. In silico studies were performed on several peptides that affect VEGFR2 in both stimulating and inhibitory ways. This investigation aims to examine the molecular properties of VEGFR2, a molecule primarily involved in the processes of vasculogenesis and angiogenesis. These relationships were defined by the interactions between Vascular Endothelial Growth Factor receptor 2 (VEGFR2) and the structural features of the systems. The chemical space of the inhibitory peptides and stimulators was described using topological and energetic properties. Furthermore, chimeric models of stimulating and inhibitory proteins (for VEGFR2) were computed using the protein system structures. The interaction between the chimeric proteins and VEGFR was computed. The chemical space was further characterized using complex manifolds and high-dimensional data visualization. The results show that a slightly similar chemical area is shared by VEGFR2 and stimulating and inhibitory proteins. On the other hand, the stimulator peptides and the inhibitors have distinct chemical spaces.

Keywords: angiogenesis; chimeric protein; docking; molecular modeling; peripheral artery disease; vascular morphogenesis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Homology models of PDGF C, PIGF, PDGF D, and Vasostatin.
Figure 2
Figure 2
(a) VEGFR2 is represented as a ribbon; cavity 1 is defined as water clusters (molecules of water shown in grey); the coordinates of the binding site are shown by a black arrow (x = 29.04 Å; y = −36.68 Å; z = −18.54 Å); details of the binding site are also represented; (b) binding site of VEGFR2 detail and binding site space filling; (c) VEGFR2 docked with 2H-chromen-2-one (slightly moved compared to (a) to show the ligand—colored in pink—in the binding pocket).
Figure 3
Figure 3
Docking energies of VEGFR2 against a set of Chembl1 structures. For ligands 1–27, see Supplementary File S1 and Section 4. E_total energy (kcal/mol); E sol—solvation energy (Kcal/mol); E ang—angulation energy (kcal/mol) (ligand names and structures can be found in Supplementary File S4).
Figure 4
Figure 4
The protein–protein complex of an inhibitory and stimulant protein is docked with VEGFR2 represented in ribbons.
Figure 5
Figure 5
VEGFR2 inhibitor complex energies (kcal/mol): E−the total complex energy; E sol—solvation energy; E ang—angular energy.
Figure 6
Figure 6
VEGFR2 stimulator complex energies (kcal/mol). E ref—the total complex energy; E sol—−solvation energy; E ang—angular energy.
Figure 7
Figure 7
Chimeric protein models for the inhibitory and stimulant proteins.The models are represented as ribbons.
Figure 8
Figure 8
Aa composition (%) of inhibitory and stimulant chimeric models.
Figure 9
Figure 9
Chemical space of inhibitory and stimulant proteins of angiogenesis. The chemical space is characterized by the six molecular descriptors: mol weight, number of H bond acceptors, number of H bond donors, polar surface area, shape attribute, sum of degrees, and sum of valence degrees. The chemical space is represented as radar plots.
Figure 9
Figure 9
Chemical space of inhibitory and stimulant proteins of angiogenesis. The chemical space is characterized by the six molecular descriptors: mol weight, number of H bond acceptors, number of H bond donors, polar surface area, shape attribute, sum of degrees, and sum of valence degrees. The chemical space is represented as radar plots.
Figure 10
Figure 10
Angiogenesis chemical space of inhibitory and stimulating proteins in chimeric models characterized by molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors, shape attribute of each molecule, polar surface, and the sum of degrees.
Figure 11
Figure 11
C-alpha distance map plot of inhibitory and stimulant chimeric models together with PEDF (as an inhibitor example) and Angiopoietin 1 (as a stimulant example).
Figure 12
Figure 12
Chimeric and stimulant model multidimensional data represented as scatter plots.
Figure 12
Figure 12
Chimeric and stimulant model multidimensional data represented as scatter plots.
Figure 13
Figure 13
Two-dimensional complex map of the six-degree polynomial equation: (a) inhibitory space equation; (b) stimulant space equation; (c) combined space equation.
Figure 14
Figure 14
Ramachandran plots for the homology models used in the computations.
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