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Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera's key metabolite Withaferin A.

Saha S, Islam MK, Shilpi JA, Hasan S - In Silico Pharmacol (2013)

Bottom Line: To avoid such side-effects, new insight is required to find potential compounds as anti-VEGF from natural sources.Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab.Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential interaction with VEGF.

View Article: PubMed Central - PubMed

Affiliation: Pharmacy Discipline, Life Science School, Khulna University, Khulna, 9208 Bangladesh.

ABSTRACT

Purpose: Angiogenesis, or new blood vessel formation from existing one, plays both beneficial and detrimental roles in living organisms in different aspects. Vascular endothelial growth factor (VEGF), a signal protein, well established as key regulator of vasculogenesis and angiogenesis. VEGF ensures oxygen supply to the tissues when blood supply is not adequate, or tissue environment is in hypoxic condition. Limited expression of VEGF is necessary, but if it is over expressed, then it can lead to serious disease like cancer. Cancers that have ability to express VEGF are more efficient to grow and metastasize because solid cancers cannot grow larger than a limited size without adequate blood and oxygen supply. Anti-VEGF drugs are already available in the market to control angiogenesis, but they are often associated with severe side-effects like fetal bleeding and proteinuria in the large number of patients. To avoid such side-effects, new insight is required to find potential compounds as anti-VEGF from natural sources. In the present investigation, molecular docking studies were carried out to find the potentiality of Withaferin A, a key metabolite of Withania somnifera, as an inhibitor of VEGF.

Methods: Molecular Docking studies were performed in DockingServer and SwissDock. Bevacizumab, a commercial anti-VEGF drug, was used as reference to compare the activity of Withaferin A. X-ray crystallographic structure of VEGF, was retrieved from Protein Data Bank (PDB), and used as drug target protein. Structure of Withaferin A and Bevacizumab was obtained from PubChem and ZINC databases. Molecular visualization was performed using UCSF Chimera.

Results: Withaferin A showed favorable binding with VEGF with low binding energy in comparison to Bevacizumab. Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab.

Conclusions: Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential interaction with VEGF. This scientific hypothesis might provide a better insight to control angiogenesis as well as to control solid cancer growth and metastasis.

No MeSH data available.


Related in: MedlinePlus

Visualization of Withaferin A/Bevacizumab-VEGF protein interaction profile by SwissDock.(A) Visualization of Withaferin A-VEGF interaction by SwissDock. (B) Visualization of Bevacizumab-VEGF interaction by SwissDock. Visualization is performed using UCSF Chimera.
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Fig6: Visualization of Withaferin A/Bevacizumab-VEGF protein interaction profile by SwissDock.(A) Visualization of Withaferin A-VEGF interaction by SwissDock. (B) Visualization of Bevacizumab-VEGF interaction by SwissDock. Visualization is performed using UCSF Chimera.

Mentions: In the studies by SwissDock, FullFitness and Gibbs free energy (ΔG) of each run (250 runs) of the docking were evaluated. Favorable binding modes were scored based on FullFitness and cluster formation. Ranking of the cluster was performed using the value of FullFitness. Tables 3 and 4 shows the clustering results obtained from the docking of the ligands into VEGF protein. Withaferin A showed FullFitness of -1948.69 kcal/mol and estimated ΔG of -7.24 kcal/mol for the most favorable interaction, whereas Bevacizumab showed FullFitness of -2221.84 kcal/mol and ΔG of -7.56 kcal/mol. Figure 6 shows the visualization of the most energetically favorable binding of the legands into the protein VEGF.Table 3


Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera's key metabolite Withaferin A.

Saha S, Islam MK, Shilpi JA, Hasan S - In Silico Pharmacol (2013)

Visualization of Withaferin A/Bevacizumab-VEGF protein interaction profile by SwissDock.(A) Visualization of Withaferin A-VEGF interaction by SwissDock. (B) Visualization of Bevacizumab-VEGF interaction by SwissDock. Visualization is performed using UCSF Chimera.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230651&req=5

Fig6: Visualization of Withaferin A/Bevacizumab-VEGF protein interaction profile by SwissDock.(A) Visualization of Withaferin A-VEGF interaction by SwissDock. (B) Visualization of Bevacizumab-VEGF interaction by SwissDock. Visualization is performed using UCSF Chimera.
Mentions: In the studies by SwissDock, FullFitness and Gibbs free energy (ΔG) of each run (250 runs) of the docking were evaluated. Favorable binding modes were scored based on FullFitness and cluster formation. Ranking of the cluster was performed using the value of FullFitness. Tables 3 and 4 shows the clustering results obtained from the docking of the ligands into VEGF protein. Withaferin A showed FullFitness of -1948.69 kcal/mol and estimated ΔG of -7.24 kcal/mol for the most favorable interaction, whereas Bevacizumab showed FullFitness of -2221.84 kcal/mol and ΔG of -7.56 kcal/mol. Figure 6 shows the visualization of the most energetically favorable binding of the legands into the protein VEGF.Table 3

Bottom Line: To avoid such side-effects, new insight is required to find potential compounds as anti-VEGF from natural sources.Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab.Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential interaction with VEGF.

View Article: PubMed Central - PubMed

Affiliation: Pharmacy Discipline, Life Science School, Khulna University, Khulna, 9208 Bangladesh.

ABSTRACT

Purpose: Angiogenesis, or new blood vessel formation from existing one, plays both beneficial and detrimental roles in living organisms in different aspects. Vascular endothelial growth factor (VEGF), a signal protein, well established as key regulator of vasculogenesis and angiogenesis. VEGF ensures oxygen supply to the tissues when blood supply is not adequate, or tissue environment is in hypoxic condition. Limited expression of VEGF is necessary, but if it is over expressed, then it can lead to serious disease like cancer. Cancers that have ability to express VEGF are more efficient to grow and metastasize because solid cancers cannot grow larger than a limited size without adequate blood and oxygen supply. Anti-VEGF drugs are already available in the market to control angiogenesis, but they are often associated with severe side-effects like fetal bleeding and proteinuria in the large number of patients. To avoid such side-effects, new insight is required to find potential compounds as anti-VEGF from natural sources. In the present investigation, molecular docking studies were carried out to find the potentiality of Withaferin A, a key metabolite of Withania somnifera, as an inhibitor of VEGF.

Methods: Molecular Docking studies were performed in DockingServer and SwissDock. Bevacizumab, a commercial anti-VEGF drug, was used as reference to compare the activity of Withaferin A. X-ray crystallographic structure of VEGF, was retrieved from Protein Data Bank (PDB), and used as drug target protein. Structure of Withaferin A and Bevacizumab was obtained from PubChem and ZINC databases. Molecular visualization was performed using UCSF Chimera.

Results: Withaferin A showed favorable binding with VEGF with low binding energy in comparison to Bevacizumab. Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab.

Conclusions: Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential interaction with VEGF. This scientific hypothesis might provide a better insight to control angiogenesis as well as to control solid cancer growth and metastasis.

No MeSH data available.


Related in: MedlinePlus