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Effects of P-Glycoprotein on the Transport of DL0410, a Potential Multifunctional Anti-Alzheimer Agent.
- Source :
-
Molecules . Aug2017, Vol. 22 Issue 8, p1246. 12p. 3 Diagrams, 3 Charts, 4 Graphs. - Publication Year :
- 2017
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 22
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Molecules
- Publication Type :
- Academic Journal
- Accession number :
- 124869511
- Full Text :
- https://doi.org/10.3390/molecules22081246