Abstract
Background
P-glycoprotein (P-gp) is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity.
Objective
To evaluate the important amino acid residues within nucleotide binding domain 1 (NBD1) of P-gp that play a key role in molecular interactions with flavonoids using structure-based pharmacophore model.
Methods
In the molecular docking with NBD1 models, a putative binding site of flavonoids was proposed and compared with the site for ATP. The binding modes for ligands were achieved using LigandScout to generate the P-gp–flavonoid pharmacophore models.
Results
The binding pocket for flavonoids was investigated and found these inhibitors compete with the ATP for binding site in NBD1 including the NBD1 amino acid residues identified by the in silico techniques to be involved in the hydrogen bonding and van der Waals (hydrophobic) interactions with flavonoids.
Conclusion
These flavonoids occupy with the same binding site of ATP in NBD1 proffering that they may act as an ATP competitive inhibitor.
References
Badhan R, Penny J (2006). In silico modelling of the interaction of flavonoids with human P-glycoprotein nucleotide-binding domain. Eur J Med Chem, 41(3): 285–295
Chung S Y, Sung M K, Kim N H, Jang J O, Go E J, Lee H J (2005). Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch Pharm Res, 28(7): 823–828
El-Readi M Z, Hamdan D, Farrag N, El-Shazly A, Wink M (2010). Inhibition of P-glycoprotein activity by limonin and other secondary metabolites from Citrus species in human colon and leukaemia cell lines. Eur J Pharmacol, 626(2–3): 139–145
Gadhe C G, Kothandan G, Cho S J (2013). In silico study of desmosdumotin as an anticancer agent: homology modeling, docking and molecular dynamics simulation approach. Anticancer Agents Med Chem, 13(10): 1636–1644
Gyémánt N, Tanaka M, Antus S, Hohmann J, Csuka O, Mándoky L, Molnár J (2005). In vitro search for synergy between flavonoids and epirubicin on multidrug-resistant cancer cells. In Vivo, 19(2): 367–374
Kitagawa S, Nabekura T, Kamiyama S (2004). Inhibition of Pglycoprotein function by tea catechins in KB-C2 cells. J Pharm Pharmacol, 56(8): 1001–1005
Li X, Hu J, Wang B, Sheng L, Liu Z, Yang S, Li Y (2014). Inhibitory effects of herbal constituents on P-glycoprotein in vitro and in vivo: herb-drug interactions mediated via P-gp. Toxicol Appl Pharmacol, 275(2): 163–175
Lopez D, Martinez-Luis S (2014). Marine natural products with Pglycoprotein inhibitor properties. Mar Drugs, 12(1): 525–546
Martins A, Vasas A, Schelz Z, Viveiros M, Molnár J, Hohmann J, Amaral L (2010). Constituents of Carpobrotus edulis inhibit Pglycoprotein of MDR1-transfected mouse lymphoma cells. Anticancer Res, 30(3): 829–835
Wolber G, Langer T (2005). LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model, 45(1): 160–169
Wongrattanakamon P, Lee V S, Nimmanpipug P, Jiranusornkul S (2016). Nucleotide-binding domain 1 modelling: A novel molecular docking approach for screening of P-glycoprotein inhibitory activity of bioflavonoids. Chemical Data Collections, doi: 10.1016/j.cdc.2016.06.001
Zhang S, Morris M E (2003). Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther, 304(3): 1258–1267
Author information
Authors and Affiliations
Corresponding authors
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Wongrattanakamon, P., Lee, V.S., Nimmanpipug, P. et al. Nucleotide binding domain 1 pharmacophore modeling for visualization and analysis of P-glycoprotein–flavonoid molecular interactions. Front. Biol. 11, 391–395 (2016). https://doi.org/10.1007/s11515-016-1421-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11515-016-1421-3