Nucleotide binding domain 1 pharmacophore modeling for visualization and analysis of P-glycoprotein–flavonoid molecular interactions

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.

Keywords

P-glycoprotein / Nucleotide-binding domain 1 / pharmacophore model / flavonoid / competitive inhibition / herb-drug interaction

References

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] Kitagawa S, Nabekura T, Kamiyama S (2004). Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells. J Pharm Pharmacol, 56(8): 1001–1005

[7] 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

[8] Lopez D, Martinez-Luis S (2014). Marine natural products with P-glycoprotein inhibitor properties. Mar Drugs, 12(1): 525–546

[9] Martins A, Vasas A, Schelz Z, Viveiros M, Molnár J, Hohmann J, Amaral L (2010). Constituents of Carpobrotus edulis inhibit P-glycoprotein of MDR1-transfected mouse lymphoma cells. Anticancer Res, 30(3): 829–835

[10] 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

[11] 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,

[12] 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

Acknowledgements

This paper is part of the Ph.D. thesis which was implemented with partial financial support number 32/2559 from the Graduate School, Chiang Mai University, Thailand. The authors would like to thank Inte:Ligand Software-Entwicklungs und Consulting GmbH for providing an academic free license for LigandScout 3.12.

Compliance with ethics guidelines

Pathomwat Wongrattanakamon, Vannajan Sanghiran Lee, Piyarat Nimmanpipug and Supat Jiranusornkul declares that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

2016 Higher Education Press and Springer-Verlag Berlin Heidelberg