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Exploring the Molecular Interactions of 7,8-Dihydroxyflavone and Its Derivatives with TrkB and VEGFR2 Proteins.

Chitranshi N, Gupta V, Kumar S, Graham SL - Int J Mol Sci (2015)

Bottom Line: Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors.Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain.Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia. nitin.chitranshi@students.mq.edu.au.

ABSTRACT
7,8-dihydroxyflavone (7,8-DHF) is a TrkB receptor agonist, and treatment with this flavonoid derivative brings about an enhanced TrkB phosphorylation and promotes downstream cellular signalling. Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors. VEGFR2 is one of the important receptors involved in the regulation of vasculogenesis and angiogenesis and has also been implicated to exhibit various neuroprotective roles. Its upregulation and uncontrolled activity is associated with a range of pathological conditions such as age-related macular degeneration and various proliferative disorders. In this study, we investigated molecular interactions of 7,8-DHF and its derivatives with both the TrkB receptor as well as VEGFR2. Using a combination of molecular docking and computational mapping tools involving molecular dynamics approaches we have elucidated additional residues and binding energies involved in 7,8-DHF interactions with the TrkB Ig2 domain and VEGFR2. Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain. Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.

No MeSH data available.


Related in: MedlinePlus

Interaction and binding mode of 7,8-dihydroxyflavone (7,8-DHF) with TrkB and VEGFR2. (A) Docking of TrkB (ribbon structure) with the 7,8-DHF (wire-frame) showing critical residues involved in interaction; (B) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-TrkB complex; (C) Docking of VEGFR2 (ribbon structure) with the 7,8-DHF (wire-frame) highlighting important residues involved in interaction; (D) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-VEGFR2 complex. Red (α-helix), cyan (β-sheets) grey (random coil). Green strong line denotes the hydrogen bonding and pink dashed line reflects pi–sigma interactions and stacking. The images were generated with the Discovery Studio 4.0 Client (Accelrys, Inc., San Diego, CA, USA).
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ijms-16-21087-f001: Interaction and binding mode of 7,8-dihydroxyflavone (7,8-DHF) with TrkB and VEGFR2. (A) Docking of TrkB (ribbon structure) with the 7,8-DHF (wire-frame) showing critical residues involved in interaction; (B) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-TrkB complex; (C) Docking of VEGFR2 (ribbon structure) with the 7,8-DHF (wire-frame) highlighting important residues involved in interaction; (D) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-VEGFR2 complex. Red (α-helix), cyan (β-sheets) grey (random coil). Green strong line denotes the hydrogen bonding and pink dashed line reflects pi–sigma interactions and stacking. The images were generated with the Discovery Studio 4.0 Client (Accelrys, Inc., San Diego, CA, USA).

Mentions: The interactions of 7,8-DHF with TrkB and theVEGFR2 receptor were analysed using a molecular docking approach. TrkB-domain5 (TrkB-D5) and VEGFR2 structures were subjected to 7,8-DHF binding in silico using AutoDock4.2 to reveal the best binding modes of 7,8-DHF. Our studies revealed that the binding site of TrkB-D5 comprised of Lys312, Pro313, Ala314, Leu315, Trp317, Ile323, Leu324, Glu326, Cys331, Thr332, Lys333, Ile334 and Tyr342 residues. Hydrogen bonding with Leu315 and Ile334 indicated these to be critical residues involved in interaction with 7,8-DHF (Figure 1A,B). In the case of 7,8-DHF docking with VEGFR2, the binding site was selected based on its previously reported interactions with 2-anilino-5-aryl-oxazole (AAX), a VEGFR2 inhibitor (PDB id. 1Y6B). The amino acids Leu838, Arg840 Ile847, Ala864, Val865, Lys866, Glu883, Ile913, Val914, Phe916, Cys917, Lys918, Asn921, Thr924, Arg1030, and Leu1033 were observed to comprise the binding site of VEGFR2 protein. AAX extraction and docking of 7,8-DHF showed key hydrogen bond interaction with Cys917 residues of VEGFR2 protein (Figure 1C,D).


Exploring the Molecular Interactions of 7,8-Dihydroxyflavone and Its Derivatives with TrkB and VEGFR2 Proteins.

Chitranshi N, Gupta V, Kumar S, Graham SL - Int J Mol Sci (2015)

Interaction and binding mode of 7,8-dihydroxyflavone (7,8-DHF) with TrkB and VEGFR2. (A) Docking of TrkB (ribbon structure) with the 7,8-DHF (wire-frame) showing critical residues involved in interaction; (B) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-TrkB complex; (C) Docking of VEGFR2 (ribbon structure) with the 7,8-DHF (wire-frame) highlighting important residues involved in interaction; (D) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-VEGFR2 complex. Red (α-helix), cyan (β-sheets) grey (random coil). Green strong line denotes the hydrogen bonding and pink dashed line reflects pi–sigma interactions and stacking. The images were generated with the Discovery Studio 4.0 Client (Accelrys, Inc., San Diego, CA, USA).
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Related In: Results  -  Collection

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ijms-16-21087-f001: Interaction and binding mode of 7,8-dihydroxyflavone (7,8-DHF) with TrkB and VEGFR2. (A) Docking of TrkB (ribbon structure) with the 7,8-DHF (wire-frame) showing critical residues involved in interaction; (B) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-TrkB complex; (C) Docking of VEGFR2 (ribbon structure) with the 7,8-DHF (wire-frame) highlighting important residues involved in interaction; (D) Enlarged view of the interaction pocket within 5.5 Å around the ligand, 7,8-DHF-VEGFR2 complex. Red (α-helix), cyan (β-sheets) grey (random coil). Green strong line denotes the hydrogen bonding and pink dashed line reflects pi–sigma interactions and stacking. The images were generated with the Discovery Studio 4.0 Client (Accelrys, Inc., San Diego, CA, USA).
Mentions: The interactions of 7,8-DHF with TrkB and theVEGFR2 receptor were analysed using a molecular docking approach. TrkB-domain5 (TrkB-D5) and VEGFR2 structures were subjected to 7,8-DHF binding in silico using AutoDock4.2 to reveal the best binding modes of 7,8-DHF. Our studies revealed that the binding site of TrkB-D5 comprised of Lys312, Pro313, Ala314, Leu315, Trp317, Ile323, Leu324, Glu326, Cys331, Thr332, Lys333, Ile334 and Tyr342 residues. Hydrogen bonding with Leu315 and Ile334 indicated these to be critical residues involved in interaction with 7,8-DHF (Figure 1A,B). In the case of 7,8-DHF docking with VEGFR2, the binding site was selected based on its previously reported interactions with 2-anilino-5-aryl-oxazole (AAX), a VEGFR2 inhibitor (PDB id. 1Y6B). The amino acids Leu838, Arg840 Ile847, Ala864, Val865, Lys866, Glu883, Ile913, Val914, Phe916, Cys917, Lys918, Asn921, Thr924, Arg1030, and Leu1033 were observed to comprise the binding site of VEGFR2 protein. AAX extraction and docking of 7,8-DHF showed key hydrogen bond interaction with Cys917 residues of VEGFR2 protein (Figure 1C,D).

Bottom Line: Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors.Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain.Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia. nitin.chitranshi@students.mq.edu.au.

ABSTRACT
7,8-dihydroxyflavone (7,8-DHF) is a TrkB receptor agonist, and treatment with this flavonoid derivative brings about an enhanced TrkB phosphorylation and promotes downstream cellular signalling. Flavonoids are also known to exert an inhibitory effect on the vascular endothelial growth factor receptor (VEGFR) family of tyrosine kinase receptors. VEGFR2 is one of the important receptors involved in the regulation of vasculogenesis and angiogenesis and has also been implicated to exhibit various neuroprotective roles. Its upregulation and uncontrolled activity is associated with a range of pathological conditions such as age-related macular degeneration and various proliferative disorders. In this study, we investigated molecular interactions of 7,8-DHF and its derivatives with both the TrkB receptor as well as VEGFR2. Using a combination of molecular docking and computational mapping tools involving molecular dynamics approaches we have elucidated additional residues and binding energies involved in 7,8-DHF interactions with the TrkB Ig2 domain and VEGFR2. Our investigations have revealed for the first time that 7,8-DHF has dual biochemical action and its treatment may have divergent effects on the TrkB via its extracellular Ig2 domain and on the VEGFR2 receptor through the intracellular kinase domain. Contrary to its agonistic effects on the TrkB receptor, 7,8-DHF was found to downregulate VEGFR2 phosphorylation both in 661W photoreceptor cells and in retinal tissue.

No MeSH data available.


Related in: MedlinePlus