Identification of possible binding sites for morphine and nicardipine on the multidrug transporter P-Glycoprotein using umbrella sampling techniques

Subramanian, Nandhitha, Condic-Jurkic, Karmen, Mark, Alan E. and O'Mara, Megan L. (2015) Identification of possible binding sites for morphine and nicardipine on the multidrug transporter P-Glycoprotein using umbrella sampling techniques. Journal of Chemical Information and Modeling, 55 6: 1202-1217. doi:10.1021/ci5007382


Author Subramanian, Nandhitha
Condic-Jurkic, Karmen
Mark, Alan E.
O'Mara, Megan L.
Title Identification of possible binding sites for morphine and nicardipine on the multidrug transporter P-Glycoprotein using umbrella sampling techniques
Journal name Journal of Chemical Information and Modeling   Check publisher's open access policy
ISSN 1520-5142
1549-9596
Publication date 2015-06-22
Sub-type Article (original research)
DOI 10.1021/ci5007382
Volume 55
Issue 6
Start page 1202
End page 1217
Total pages 16
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2016
Language eng
Abstract The multidrug transporter P-glycoprotein (P-gp) is central to the development of multidrug resistance in cancer. While residues essential for transport and binding have been identified, the location, composition, and specificity of potential drug binding sites are uncertain. Here molecular dynamics simulations are used to calculate the free energy profile for the binding of morphine and nicardipine to P-gp. We show that morphine and nicardipine primarily interact with key residues implicated in binding and transport from mutational studies, binding at different but overlapping sites within the transmembrane pore. Their permeation pathways were distinct but involved overlapping sets of residues. The results indicate that the binding location and permeation pathways of morphine and nicardipine are not well separated and cannot be considered as unique. This has important implications for our understanding of substrate uptake and transport by P-gp. Our results are independent of the choice of starting structure and consistent with a range of experimental studies.
Keyword Morphine
Nicardipine
P-glycoprotein
molecular dynamic simulations
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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