TITLE:
Some substrates of P-glycoprotein targeting β-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis
AUTHORS:
Tongyang Zhu, Jie Chen, Jie Yang
KEYWORDS:
P-Glycoproteins; Quantitative Structure-Activity Relationship; ATP-Binding Cassette Transporters; Multidrug Resistance; Blood-Brain Barrier
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.4 No.9,
September
3,
2013
ABSTRACT: The pathogenesis of Alzheimer’s disease (AD) putatively
involves a compromised blood-brain barrier (BBB).
In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained
increasing attention as a potential mechanism in the pathogenesis of
neurodegenerative disorders such as AD, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid
(Aβ), a neuropathological hallmark
of AD. P-glycoprotein (P-gp), a major component of the BBB, plays a role in the
etiology of AD through Aβ clearance
from the brain. Our QSAR models on a series of purine-type and propafenone-type
substrates of P-gp showed that the interaction
between P-gp and its modulators depended on Molar Refractivity, LogP,
and Shape Attribute of drugs it transports. Meanwhile, another model on BBB
partitioning of some compounds revealed that BBB partitioning relied upon the
polar surface area, LogP, Balaban Index, the
strength of a molecule combined with the membrane-water complex, and
the changeability of the structure of a solute-membrane-water complex. The predictive model on BBB partitioning contributes to the discovery of some molecules through BBB as potential AD therapeutic
drugs. Moreover, the interaction model of P-gp and modulators for treatment
of multidrug resistance (MDR) indicates the discovery of some molecules to increase
Aβ clearance from the brain and
reduce Aβ brain accumulation by regulating
BBB P-gp in the early stages of AD. The mechanism provides a new insight into the
therapeutic strategy for AD.