QSAR Model of Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain: Incorporating P-glycoprotein Efflux as a Variable

2016 ◽  
Vol 56 (11) ◽  
pp. 2225-2233 ◽  
Author(s):  
Elena Dolgikh ◽  
Ian A. Watson ◽  
Prashant V. Desai ◽  
Geri A. Sawada ◽  
Stuart Morton ◽  
...  
Keyword(s):  
Partition Coefficient ◽  
Qsar Model ◽  
P Glycoprotein ◽  
Plasma Partition Coefficient

scholarly journals Quantitative Structure–Activity Relationships for the Flavonoid-Mediated Inhibition of P-Glycoprotein in KB/MDR1 Cells

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1661 ◽  
Author(s):  
Mengmeng Xia ◽  
Yajing Fang ◽  
Weiwei Cao ◽  
Fuqiang Liang ◽  
Siyi Pan ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Quantitative Structure ◽  
Glycoprotein P ◽  
Chemotherapy Drugs ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Daily Diet ◽  
Low Toxicity

P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.

QSPR Study on n-Octanol/Water Partition Coefficient of PCDD/Fs by Three-Dimensional Holographic Vector of Atomic Interaction Field

2011 ◽  
Vol 356-360 ◽  
pp. 83-88 ◽  
Author(s):  
Shu Qiao ◽  
Kun Xie ◽  
Chuan Fu ◽  
Jie Pan
Keyword(s):  
Partition Coefficient ◽  
Organic Pollutants ◽  
Three Dimensional ◽  
Qsar Model ◽  
Atomic Interaction ◽  
Structure Property ◽  
Qspr Model ◽  
Chemical Structures ◽  
Interaction Field ◽  
Water Partition Coefficient

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) are a group of important persistent organic pollutants. Quantitative structure–property relationship (QSPR) modeling is a powerful approach for predicting the properties of environmental organic pollutants from their structure descriptors. In this study, a QSPR model is established for estimating n-octanol/water partition coefficient (log KOW) of PCDD/Fs. Three-dimensional holographic vector of atomic interaction field (3D-HoVAIF) is used to describe the chemical structures, SMR-PLS QSAR model has been created and good correlation coefficients and cross-validated correlation coefficient is obtained. Predictive capability of the models has also been demonstrated by leave-one-out cross-validation. Moreover, the estimated values have been presented for those PCDD/Fs which are lack of experimentally data by the optimum model.

scholarly journals In Vivo Red Blood Cells/Plasma Partition Coefficient of Treosulfan and Its Active Monoepoxide in Rats

2018 ◽  
Vol 43 (5) ◽  
pp. 565-571 ◽  
Author(s):  
Michał Romański ◽  
Anna Zacharzewska ◽  
Artur Teżyk ◽  
Franciszek K. Główka
Keyword(s):  
Partition Coefficient ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Plasma Partition Coefficient

scholarly journals Theoretical Prediction of the Complex P-Glycoprotein Substrate Efflux Based on the Novel Hierarchical Support Vector Regression Scheme

2018 ◽  
Author(s):  
Chun Chen ◽  
Ming-Han Lee ◽  
Ching-Feng Weng ◽  
Max K. Leong
Keyword(s):  
Support Vector Regression ◽  
Atp Hydrolysis ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Support Vector ◽  
The Novel ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Wide Range ◽  
Substrate Binding Sites

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, q2CV = 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.

scholarly journals Exploring the Monoterpene Indole Alkaloid Scaffold for Reversing P-Glycoprotein-Mediated Multidrug Resistance in Cancer

2021 ◽  
Vol 14 (9) ◽  
pp. 862
Author(s):  
David S. P. Cardoso ◽  
Nikoletta Szemerédi ◽  
Gabriella Spengler ◽  
Silva Mulhovo ◽  
Daniel J. V. A. dos Santos ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cell Model ◽  
Indole Alkaloid ◽  
2D Nmr ◽  
Qsar Model ◽  
Collateral Sensitivity ◽  
P Glycoprotein ◽  
In Silico Studies ◽  
T Lymphoma ◽  
Drug Receptor

Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans, was submitted to chemical transformation of the ketone function, yielding 19 azines (3–21) and 11 semicarbazones (22–32) bearing aliphatic or aromatic substituents. Their structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments. Compounds 3–32 were evaluated as multidrug resistance (MDR) reversers through functional and chemosensitivity assays in a human ABCB1-transfected mouse T-lymphoma cell model, overexpressing P-glycoprotein. A significant increase of P-gp inhibitory activity was observed for most derivatives, mainly those containing azine moieties with aromatic substituents. Compounds with trimethoxyphenyl (17) or naphthyl motifs (18, 19) were among the most active, exhibiting strong inhibition at 0.2 µM. Moreover, most of the derivatives showed selective antiproliferative effects toward resistant cells, having a collateral sensitivity effect. In drug combination assays, all compounds showed to interact synergistically with doxorubicin. Selected compounds (12, 17, 18, 20, and 29) were evaluated in the ATPase activity assay, in which all compounds but 12 behaved as inhibitors. To gather further insights on drug–receptor interactions, in silico studies were also addressed. A QSAR model allowed us to deduce that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors.

Age-Related Change in Tissue-to-Plasma Partition Coefficient of Cefazolin for Noneliminating Organs in the Rat

1989 ◽  
Vol 78 (7) ◽  
pp. 535-540 ◽  
Author(s):  
Akira Tsuji ◽  
Tetsuya Terasaki ◽  
Norishige Imaeda ◽  
Kazunori Nishide ◽  
Ikumi Tamai
Keyword(s):  
Partition Coefficient ◽  
Age Related ◽  
Plasma Partition Coefficient

scholarly journals Theoretical Prediction of the Complex P-Glycoprotein Substrate Efflux Based on the Novel Hierarchical Support Vector Regression Scheme

Molecules ◽  
2018 ◽  
Vol 23 (7) ◽  
pp. 1820 ◽  
Author(s):  
Chun Chen ◽  
Ming-Han Lee ◽  
Ching-Feng Weng ◽  
Max Leong
Keyword(s):  
Support Vector Regression ◽  
Atp Hydrolysis ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Support Vector ◽  
The Novel ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Wide Range ◽  
Substrate Binding Sites

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, qCV2 = 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.

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