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Molecules 2017, 22(8), 1246; doi:10.3390/molecules22081246

Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent

1
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street, Beijing 100050, China
2
Beijing Key Laboratory of Drug Target Research and Drug Screening, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
*
Authors to whom correspondence should be addressed.
Received: 5 July 2017 / Revised: 17 July 2017 / Accepted: 23 July 2017 / Published: 25 July 2017
(This article belongs to the Special Issue Neuroprotective Agents)
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Abstract

In our study, we attempted to investigate the influences of P-glycoprotein (P-gp) on DL0410, a novel synthetic molecule for Alzheimer’s disease (AD) treatment, for intestinal absorption and blood-brain barrier permeability in vitro and related binding mechanisms in silico. Caco-2, MDCK, and MDCK-MDR1 cells were utilized for transport studies, and homology modelling of human P-gp was built for further docking study to uncover the binding mode of DL0410. The results showed that the apparent permeability (Papp) value of DL0410 was approximately 1 × 10−6 cm/s, indicating the low permeability of DL0410. With the presence of verapamil, the directional transport of DL0410 disappeared in Caco-2 and MDCK-MDR1 cells, suggesting that DL0410 should be a substrate of P-gp, which was also confirmed by P-gp ATPase assay. In addition, DL0410 could competitively inhibit the transport of Rho123, a P-gp known substrate. According to molecular docking, we also found that DL0410 could bind to the drug binding pocket (DBP), but not the nucleotide binding domain (NBD). In conclusion, DL0410 was a substrate as well as a competitive inhibitor of P-gp, and P-gp had a remarkable impact on the intestine and brain permeability of DL0410, which is of significance for drug research and development. View Full-Text
Keywords: Alzheimer’s disease; DL0410; P-glycoprotein; homology modelling; molecular docking Alzheimer’s disease; DL0410; P-glycoprotein; homology modelling; molecular docking
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Pang, X.; Wang, L.; Kang, D.; Zhao, Y.; Wu, S.; Liu, A.-L.; Du, G.-H. Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent. Molecules 2017, 22, 1246.

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