Structural Mapping of Inhibitors Binding Sites on P-glycoprotein: Mechanism of Inhibition of P-Glycoprotein by Herbal Isoflavones.
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Date
2013-10
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Abstract
Understanding the pattern of inhibitors binding to p-glycoprotein (Pgp).
Study Design: Pgp is an ATP dependent transporter protein, responsible for multi-drug
resistance in metastatic tumors. It removes toxins by exporting a variety of structurally
unrelated compounds outside the cells, which make Pgp a promising target for designing
anti cancer supplementary therapeutic molecules. Isoflavones are present in soyabean
and other herbal extracts. The idea was to explore inhibitor binding sites on Pgp to find
hotspots which eventually may prove useful in designing compounds with higher specificity
and affinity.
Place and Duration of Study: School of Biotechnology, Gautam Buddha University,
Greater Noida, between February 2012 and December 2012.
Methodology: The biochemical nature of binding of isoflavones to Pgp has been
extensively studied, but the atomic details of their interactions were not understood.
Therefore, we have used in silico methods to study binding of eleven isoflavones to Pgp.
The docking studies were performed using grid-based ligand docking with energetic
(GLIDE).
Results: Isoflavones binds at two slightly distinct sites perpendicular to each other,
present in the large hydrophobic cavity of Pgp. Three isoflavones bind to site 1, whereas eight isoflavones bind to site 2 by forming van der Waals and H-bonded interactions. Both
the sites are highly hydrophobic in nature and are contributed mainly by side chain of non
polar residues present on twelve transmembrane -helices. Site 1 has minimum
dimension of 7.5Å and maximum as 22Å whereas, site 2 is wider and deeper than site1.
One sidewall of the site 2 is formed by polar amino acid residues of helix H12, which
makes several hydrogen bonds with ligands.
Conclusion: Structure analysis revealed that addition of polar group to hydrophobic ligand
may enhance its binding affinity for Pgp, which may be used for designing potent inhibitors
to find lead compounds for drug design.
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Keywords
Multidrug resistance, P-glycoprotein, isoflavones, molecular docking
Citation
Arora Neha, Sahi Shakti, Singh Nagendra. Structural Mapping of Inhibitors Binding Sites on P-glycoprotein: Mechanism of Inhibition of P-Glycoprotein by Herbal Isoflavones. International Journal of Biochemistry Research & Review 2013 Oct-Dec ; 3 (4) : 421-435.