Year: 2026
Type: preprint
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.
Source: ChemRxiv
Institution: Inje University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221546282