Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier

Christian Jorgensen; Martin B. Ulmschneider; Peter C. Searson

doi:10.1021/acs.jmedchem.3c01069

Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier

Christian Jorgensen, Martin B. Ulmschneider, Peter C. Searson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

We report molecular dynamics simulations of rhodamine entry into the central binding cavity of P-gp in the inward open conformation. Rhodamine can enter the inner volume via passive transport across the luminal membrane or lateral diffusion in the lipid bilayer. Entry into the inner volume is determined by the aperture angle at the apex of the protein, with a critical angle of 27° for rhodamine. The central binding cavity has an aqueous phase with a few lipids, which significantly reduces substrate diffusion. Within the central binding cavity, we identified regions with relatively weak binding, suggesting that the combination of reduced mobility and weak substrate binding confines rhodamine to enable the completion of the efflux cycle. Tariquidar, a P-gp inhibitor, aggregates at the lower arms of the P-gp, suggesting that inhibition involves steric hindrance of entry into the inner volume and/or steric hindrance of access of ATP to the nucleotide-binding domains.

Original language	English
Pages (from-to)	16615-16627
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	24
DOIs	https://doi.org/10.1021/acs.jmedchem.3c01069
Publication status	Published - 28 Dec 2023

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title = "Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier",

abstract = "We report molecular dynamics simulations of rhodamine entry into the central binding cavity of P-gp in the inward open conformation. Rhodamine can enter the inner volume via passive transport across the luminal membrane or lateral diffusion in the lipid bilayer. Entry into the inner volume is determined by the aperture angle at the apex of the protein, with a critical angle of 27° for rhodamine. The central binding cavity has an aqueous phase with a few lipids, which significantly reduces substrate diffusion. Within the central binding cavity, we identified regions with relatively weak binding, suggesting that the combination of reduced mobility and weak substrate binding confines rhodamine to enable the completion of the efflux cycle. Tariquidar, a P-gp inhibitor, aggregates at the lower arms of the P-gp, suggesting that inhibition involves steric hindrance of entry into the inner volume and/or steric hindrance of access of ATP to the nucleotide-binding domains.",

author = "Christian Jorgensen and Ulmschneider, {Martin B.} and Searson, {Peter C.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

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doi = "10.1021/acs.jmedchem.3c01069",

language = "English",

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T1 - Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier

AU - Jorgensen, Christian

AU - Ulmschneider, Martin B.

AU - Searson, Peter C.

PY - 2023/12/28

Y1 - 2023/12/28

N2 - We report molecular dynamics simulations of rhodamine entry into the central binding cavity of P-gp in the inward open conformation. Rhodamine can enter the inner volume via passive transport across the luminal membrane or lateral diffusion in the lipid bilayer. Entry into the inner volume is determined by the aperture angle at the apex of the protein, with a critical angle of 27° for rhodamine. The central binding cavity has an aqueous phase with a few lipids, which significantly reduces substrate diffusion. Within the central binding cavity, we identified regions with relatively weak binding, suggesting that the combination of reduced mobility and weak substrate binding confines rhodamine to enable the completion of the efflux cycle. Tariquidar, a P-gp inhibitor, aggregates at the lower arms of the P-gp, suggesting that inhibition involves steric hindrance of entry into the inner volume and/or steric hindrance of access of ATP to the nucleotide-binding domains.

AB - We report molecular dynamics simulations of rhodamine entry into the central binding cavity of P-gp in the inward open conformation. Rhodamine can enter the inner volume via passive transport across the luminal membrane or lateral diffusion in the lipid bilayer. Entry into the inner volume is determined by the aperture angle at the apex of the protein, with a critical angle of 27° for rhodamine. The central binding cavity has an aqueous phase with a few lipids, which significantly reduces substrate diffusion. Within the central binding cavity, we identified regions with relatively weak binding, suggesting that the combination of reduced mobility and weak substrate binding confines rhodamine to enable the completion of the efflux cycle. Tariquidar, a P-gp inhibitor, aggregates at the lower arms of the P-gp, suggesting that inhibition involves steric hindrance of entry into the inner volume and/or steric hindrance of access of ATP to the nucleotide-binding domains.

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SN - 0022-2623

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Modeling Substrate Entry into the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier

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