Abstract
P-glycoprotein (P-gp), a membrane-bound transporter, can eliminate xenobiotics by transporting them out of the cells or blood–brain barrier (BBB) at the expense of ATP hydrolysis. Thus, P-gp mediated efflux plays a pivotal role in altering the absorption and disposition of a wide range of substrates. Nevertheless, the mechanism of P-gp substrate efflux is rather complex since it can take place through active transport and passive permeability in addition to multiple P-gp substrate binding sites. A nonlinear quantitative structure–activity relationship (QSAR) model was developed in this study using the novel machine learning-based hierarchical support vector regression (HSVR) scheme to explore the perplexing relationships between descriptors and efflux ratio. The predictions by HSVR were found to be in good agreement with the observed values for the molecules in the training set (n = 50, r2 = 0.96, = 0.94, RMSE = 0.10, s = 0.10) and test set (n = 13, q2 = 0.80–0.87, RMSE = 0.21, s = 0.22). When subjected to a variety of statistical validations, the developed HSVR model consistently met the most stringent criteria. A mock test also asserted the predictivity of HSVR. Consequently, this HSVR model can be adopted to facilitate drug discovery and development.
Highlights
Permeability glycoprotein known as P-glycoprotein (P-gp), which belongs to the ATP-binding cassette (ABC) superfamily of transporters, can actively transport a wide range of structurally and mechanistically diverse endogenous and xenobiotic chemical agents across the cell membrane at the energy expense of ATP hydrolysis [1]
P-gp substrate efflux can be a major obstacle in the success of central nervous system (CNS)-targeted therapeutic delivery as well as a critical pharmacokinetic factor for causing drug–drug interaction (DDI)
P-gp substrate efflux is of critical importance to drug discovery and development regardless of CNS drugs or non-CNS
Summary
Permeability glycoprotein known as P-glycoprotein (P-gp), which belongs to the ATP-binding cassette (ABC) superfamily of transporters, can actively transport a wide range of structurally and mechanistically diverse endogenous and xenobiotic chemical agents across the cell membrane at the energy expense of ATP hydrolysis [1]. P-gp, a 170-kDa plasma membrane protein encoded by the multidrug resistance gene (MDR1/ABCB1), is expressed at high levels in various tissues such as blood–brain-barriers (BBB), gastrointestinal tract (GIT), liver, kidney, and placenta [2,3,4,5,6]. P-gp plays significant roles in cell and tissue detoxification and elimination of harmful substances per se [1]. It has been found that the decreased clearance rather than production of Aβ is the primary formation of the deleterious Aβ plaques in the brain [8]. The decreased elimination of Aβ from the brain into the blood can be partially attributed to the dysfunction of P-gp function, leading to the progression of AD [9,10,11]. It has been shown that Aβ can Molecules 2018, 23, 1820; doi:10.3390/molecules23071820 www.mdpi.com/journal/molecules
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