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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

Structural presentation of ligand molecules. (A) Withaferin A falls under the family of compounds known as Withanolides, which are naturally occurring C28- steroidal lactones. The basic structure of withanolide skeleton designated as a 22-hydroxyergostan-26-oicacid-26,22-lactone. (B) 2D structure of Withaferin A. (C) 2D structure of Bevacizumab.
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Fig2: Structural presentation of ligand molecules. (A) Withaferin A falls under the family of compounds known as Withanolides, which are naturally occurring C28- steroidal lactones. The basic structure of withanolide skeleton designated as a 22-hydroxyergostan-26-oicacid-26,22-lactone. (B) 2D structure of Withaferin A. (C) 2D structure of Bevacizumab.

Mentions: The crystal structure (1.7 Å resolution) of the VEGF in complex with domain 2 of the Flt-1 receptor [PDB: 1FLT], was obtained from the Protein Data Bank (PDB) (Berman et al. 2000). Before Molecular Docking, the protein crystal structure was cleaned by removing the water molecules and hetero atoms. Missing residues (V: 1–12, W: 1–11, X: 1–131, and Y: 1–131) were supplemented to repair the crystal structure. Figure 1 shows the structure of VEGF. The ligand molecules Withaferin A [PubChem: 26759748, ZINC: 08234189] and Bevacizumab [PubChem: 24801581] were retrieved from NCBI-PubChem Compound and ZINC databases (Bolton et al. 2008; Irwin et al. 2012). Figure 2 shows the basic skeleton of Withanolides along with the structure of Withaferin A, and also the structure of Bevacizumab. The Merck molecular force field 94 (MMFF94) was utilized for energy minimization of ligands, and the charge calculation method was Gasteiger. MMFF94 was selected because it is applicable to proteins and other systems of biological significance as well as achieves MM3-like accuracy for small molecules (Halgren 1996a). Moreover, the point of view of the development of MMFF94 guided its intended use in pharmaceutical applications (Halgren 1996a). MMFF94 was developed through ab initio techniques of quantum-mechanics at its core and verified by experimental data sets (Halgren 1996a1996b1996c1996d). Halgren, pioneered a novel way to more accurately model van der Waals interactions in the development of MMFF94 (Halgren 1996a1996b1996c). The parameterization and performance of MMFF94 for intermolecular interactions has already been validated and it showed parallel performance as OPLS (Optimized Potentials for Liquid Simulations) (Halgren 1996b).Figure 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)

Structural presentation of ligand molecules. (A) Withaferin A falls under the family of compounds known as Withanolides, which are naturally occurring C28- steroidal lactones. The basic structure of withanolide skeleton designated as a 22-hydroxyergostan-26-oicacid-26,22-lactone. (B) 2D structure of Withaferin A. (C) 2D structure of Bevacizumab.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Structural presentation of ligand molecules. (A) Withaferin A falls under the family of compounds known as Withanolides, which are naturally occurring C28- steroidal lactones. The basic structure of withanolide skeleton designated as a 22-hydroxyergostan-26-oicacid-26,22-lactone. (B) 2D structure of Withaferin A. (C) 2D structure of Bevacizumab.
Mentions: The crystal structure (1.7 Å resolution) of the VEGF in complex with domain 2 of the Flt-1 receptor [PDB: 1FLT], was obtained from the Protein Data Bank (PDB) (Berman et al. 2000). Before Molecular Docking, the protein crystal structure was cleaned by removing the water molecules and hetero atoms. Missing residues (V: 1–12, W: 1–11, X: 1–131, and Y: 1–131) were supplemented to repair the crystal structure. Figure 1 shows the structure of VEGF. The ligand molecules Withaferin A [PubChem: 26759748, ZINC: 08234189] and Bevacizumab [PubChem: 24801581] were retrieved from NCBI-PubChem Compound and ZINC databases (Bolton et al. 2008; Irwin et al. 2012). Figure 2 shows the basic skeleton of Withanolides along with the structure of Withaferin A, and also the structure of Bevacizumab. The Merck molecular force field 94 (MMFF94) was utilized for energy minimization of ligands, and the charge calculation method was Gasteiger. MMFF94 was selected because it is applicable to proteins and other systems of biological significance as well as achieves MM3-like accuracy for small molecules (Halgren 1996a). Moreover, the point of view of the development of MMFF94 guided its intended use in pharmaceutical applications (Halgren 1996a). MMFF94 was developed through ab initio techniques of quantum-mechanics at its core and verified by experimental data sets (Halgren 1996a1996b1996c1996d). Halgren, pioneered a novel way to more accurately model van der Waals interactions in the development of MMFF94 (Halgren 1996a1996b1996c). The parameterization and performance of MMFF94 for intermolecular interactions has already been validated and it showed parallel performance as OPLS (Optimized Potentials for Liquid Simulations) (Halgren 1996b).Figure 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