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

doi:10.1007/s11515-016-1421-3

Front. Biol.

2016, Vol. 11

Issue (5) : 391-395 https://doi.org/10.1007/s11515-016-1421-3

SHORT COMMUNICATION

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

Pathomwat Wongrattanakamon¹(

),Vannajan Sanghiran Lee²,Piyarat Nimmanpipug³,Supat Jiranusornkul¹(

)

¹. Laboratory for Molecular Design and Simulation (LMDS), Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
². Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
³. Computational Simulation and Modelling Laboratory (CSML), Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand

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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

Corresponding Author(s): Pathomwat Wongrattanakamon,Supat Jiranusornkul

Online First Date: 20 September 2016 Issue Date: 04 November 2016

Cite this article:

Pathomwat Wongrattanakamon,Vannajan Sanghiran Lee,Piyarat Nimmanpipug, et al. Nucleotide binding domain 1 pharmacophore modeling for visualization and analysis of P-glycoprotein–flavonoid molecular interactions[J]. Front. Biol., 2016, 11(5): 391-395.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-016-1421-3
https://academic.hep.com.cn/fib/EN/Y2016/V11/I5/391

Fig.1 The example of pharmacophore models obtained from the docking complex illustrates the favorable binding position of amorphigenin with the lowest free energy of binding in the major active cavity of 4Q9H NBD1. 2D (A) and 3D (B) models show interactions between the amino acid residues and ligand formed in the cavity. Pharmacophore features in the models are colour-coded: red–hydrogen bond acceptor, and yellow–hydrophobic interactions.

Fig.2 The binding patterns of the inhibitors on 4Q9H NBD1 (gray). (A) The binding cavity occupied by the most flavonoids (green) and ATP (magenta) is shown as a close-up inside NBD1 as the major binding site except (B) 6a,12a-dehydroamorphigenin and 5HHMF (orange) bind NBD1 at their own distinct cavities.

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