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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

HB plot of Withaferin A/Bevacizumab-VEGF protein interaction profile by DockingServer.(A) HB plot structure of Withaferin A-VEGF interaction by DockingServer. Interactions with amino acids: 29: Ile, 31: Thr, 32: Leu, 50: Ser, 51: Cys, 60: Cys, 61: Cys, 64: Glu, 67: Glu, and 107: Cys. (B) HB Plot structure of Bevacizumab-VEGF interaction by DockingServer. Interactions with amino acids: 34: Asp, 36: Phe, 47: Phe, 50: Ser, and 64: Glu.
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Fig5: HB plot of Withaferin A/Bevacizumab-VEGF protein interaction profile by DockingServer.(A) HB plot structure of Withaferin A-VEGF interaction by DockingServer. Interactions with amino acids: 29: Ile, 31: Thr, 32: Leu, 50: Ser, 51: Cys, 60: Cys, 61: Cys, 64: Glu, 67: Glu, and 107: Cys. (B) HB Plot structure of Bevacizumab-VEGF interaction by DockingServer. Interactions with amino acids: 34: Asp, 36: Phe, 47: Phe, 50: Ser, and 64: Glu.

Mentions: In the studies by DockingServer, the parameters of free energy of binding, inhibition constant (Ki), total estimated energy of vdW+Hbond+desolv(EVHD), electrostatic energy, total intermolecular energy, frequency of binding, and interact surface area were evaluated to estimate the favorable binding of ligand molecules to the protein. Table 1 shows the complete profile of these parameters of both Withaferin A and Bevacizumab for their interaction with VEGF. For the most favorable binding of Withaferin A, estimated free energy of binding was of -6.09 kcal/mol, and total intermolecular energy was of -7.66 kcal/mol. In case of binding of Bevacizumab, estimated free energy of binding was of -5.59 kcal/mol, and total intermolecular energy was of -7.62 kcal/mol. In comparison to Bevacizumab, Withaferin A exhibited comparatively low free energy of interaction and intermolecular energy. Withaferin A showed the inhibition constant (ki) of 34.53 uM, whereas Bevacizumab showed Ki of 79.65 uM. Figure 3 shows the binding of the legands to the protein. A 2D plot was generated where ligand bond, non-ligand bond, and hydrogen bonds along with their length were mentioned (Figure 4). Decomposed interaction energies of hydrogen bonds, polar, hydrophobic, and other bonds are mentioned in Table 2. Additional file 1 shows the interaction profile of hydrogen bonds, polar, hydrophobic and others. A HB plot (Bikadi et al. 2007 McDonald and Thornton 1994) was generated to mention interactions with different amino acids of the protein (Figure 5).Table 1


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)

HB plot of Withaferin A/Bevacizumab-VEGF protein interaction profile by DockingServer.(A) HB plot structure of Withaferin A-VEGF interaction by DockingServer. Interactions with amino acids: 29: Ile, 31: Thr, 32: Leu, 50: Ser, 51: Cys, 60: Cys, 61: Cys, 64: Glu, 67: Glu, and 107: Cys. (B) HB Plot structure of Bevacizumab-VEGF interaction by DockingServer. Interactions with amino acids: 34: Asp, 36: Phe, 47: Phe, 50: Ser, and 64: Glu.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: HB plot of Withaferin A/Bevacizumab-VEGF protein interaction profile by DockingServer.(A) HB plot structure of Withaferin A-VEGF interaction by DockingServer. Interactions with amino acids: 29: Ile, 31: Thr, 32: Leu, 50: Ser, 51: Cys, 60: Cys, 61: Cys, 64: Glu, 67: Glu, and 107: Cys. (B) HB Plot structure of Bevacizumab-VEGF interaction by DockingServer. Interactions with amino acids: 34: Asp, 36: Phe, 47: Phe, 50: Ser, and 64: Glu.
Mentions: In the studies by DockingServer, the parameters of free energy of binding, inhibition constant (Ki), total estimated energy of vdW+Hbond+desolv(EVHD), electrostatic energy, total intermolecular energy, frequency of binding, and interact surface area were evaluated to estimate the favorable binding of ligand molecules to the protein. Table 1 shows the complete profile of these parameters of both Withaferin A and Bevacizumab for their interaction with VEGF. For the most favorable binding of Withaferin A, estimated free energy of binding was of -6.09 kcal/mol, and total intermolecular energy was of -7.66 kcal/mol. In case of binding of Bevacizumab, estimated free energy of binding was of -5.59 kcal/mol, and total intermolecular energy was of -7.62 kcal/mol. In comparison to Bevacizumab, Withaferin A exhibited comparatively low free energy of interaction and intermolecular energy. Withaferin A showed the inhibition constant (ki) of 34.53 uM, whereas Bevacizumab showed Ki of 79.65 uM. Figure 3 shows the binding of the legands to the protein. A 2D plot was generated where ligand bond, non-ligand bond, and hydrogen bonds along with their length were mentioned (Figure 4). Decomposed interaction energies of hydrogen bonds, polar, hydrophobic, and other bonds are mentioned in Table 2. Additional file 1 shows the interaction profile of hydrogen bonds, polar, hydrophobic and others. A HB plot (Bikadi et al. 2007 McDonald and Thornton 1994) was generated to mention interactions with different amino acids of the protein (Figure 5).Table 1

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