Lipid-Phase Access Does Not Explain P-Glycoprotein Substrate Selection in Matched Pairs
Abstract
The hydrophobic vacuum cleaner model holds that P-glycoprotein intercepts substrates within the lipid bilayer, which makes lipid-phase access to the transporter a candidate determinant of efflux, but the proposition has never been tested on compounds matched for the properties that otherwise dominate. We simulated nine matched molecular pairs—matched simultaneously on calculated lipophilicity, hydrogen-bond donors, polar surface area and molecular weight, and differing 5.9-to 30.1-fold in measured MDR1-MDCK efflux ratio—in a coarse-grained blood–brain barrier membrane containing human P-glycoprotein, and applied a pre-registered observable: enrichment E of substrate over non-substrate within 3.5 nm of the lateral portal axis. E bears no relation to efflux (ρ = −0.100, p = 0.80, n = 9), and the slope of unity predicted if access governed efflux lies outside the 95% interval [−0.51, +0.79], while five matched replicas put the measurement error at 3.65 times below the pair-to-pair spread, so the null is informative rather than underpowered. Selection is therefore decided after arrival at the transporter rather than during delivery to it.
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BibTeX
@misc{ullah2026lipidphase,
title = {{Lipid-Phase Access Does Not Explain P-Glycoprotein Substrate Selection in Matched Pairs}},
author = {Hayat Ullah and Khwaja Jawad and Khan Ziaullah and Md Ariful Islam Mozumder and Moon-Il Joo and Hee-Cheol Kim},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010234/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010234/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Lipid-Phase Access Does Not Explain P-Glycoprotein Substrate Selection in Matched Pairs
AU - Hayat Ullah
AU - Khwaja Jawad
AU - Khan Ziaullah
AU - Md Ariful Islam Mozumder
AU - Moon-Il Joo
AU - Hee-Cheol Kim
PY - 2026
DA - 2026/10/11
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010234/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010234/v1
AB - The hydrophobic vacuum cleaner model holds that P-glycoprotein intercepts substrates within the lipid bilayer, which makes lipid-phase access to the transporter a candidate determinant of efflux, but the proposition has never been tested on compounds matched for the properties that otherwise dominate. We simulated nine matched molecular pairs—matched simultaneously on calculated lipophilicity, hydrogen-bond donors, polar surface area and molecular weight, and differing 5.9-to 30.1-fold in measured MDR1-MDCK efflux ratio—in a coarse-grained blood–brain barrier membrane containing human P-glycoprotein, and applied a pre-registered observable: enrichment E of substrate over non-substrate within 3.5 nm of the lateral portal axis. E bears no relation to efflux (ρ = −0.100, p = 0.80, n = 9), and the slope of unity predicted if access governed efflux lies outside the 95% interval [−0.51, +0.79], while five matched replicas put the measurement error at 3.65 times below the pair-to-pair spread, so the null is informative rather than underpowered. Selection is therefore decided after arrival at the transporter rather than during delivery to it.
ER -