Research paper
In silico modelling of permeation enhancement potency in Caco-2 monolayers based on molecular descriptors and random forest

https://doi.org/10.1016/j.ejpb.2015.05.012Get rights and content
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Abstract

Structural traits of permeation enhancers are important determinants of their capacity to promote enhanced drug absorption. Therefore, in order to obtain a better understanding of structure–activity relationships for permeation enhancers, a Quantitative Structural Activity Relationship (QSAR) model has been developed.

The random forest-QSAR model was based upon Caco-2 data for 41 surfactant-like permeation enhancers from Whitehead et al. (2008) and molecular descriptors calculated from their structure.

The QSAR model was validated by two test-sets: (i) an eleven compound experimental set with Caco-2 data and (ii) nine compounds with Caco-2 data from literature. Feature contributions, a recent developed diagnostic tool, was applied to elucidate the contribution of individual molecular descriptors to the predicted potency. Feature contributions provided easy interpretable suggestions of important structural properties for potent permeation enhancers such as segregation of hydrophilic and lipophilic domains. Focusing on surfactant-like properties, it is possible to model the potency of the complex pharmaceutical excipients, permeation enhancers. For the first time, a QSAR model has been developed for permeation enhancement. The model is a valuable in silico approach for both screening of new permeation enhancers and physicochemical optimisation of surfactant enhancer systems.

Abbreviations

C6
sodium hexanoate
C8
sodium octanoate
c8G
octylglucoside
C10
sodium decanoate/caprate
c12PC
dodecylphosphocholine
c12GPC
dodecanoylglycerophosphocholine
c14GP
myristoylglycerophosphate
CART
classification and regression tree
CDC
chenodeoxycholate
DDM
dodecylmaltoside
EDTA
ethylenediaminetetraacetic acid
GCC
glycochenocholate
GH
glycyrrhizinate
LCC
lauroylcarnitinechloride
LOO-CV
leave-one-out cross validation
MOE
molecular operating environment
PCC
palmitoyl carnitine chloride
QSAR
quantitative structural activity relationship
SM
simomenine
RMSE
root mean square error
rp
Pearsons correlation coefficient
rs
Spearman rank correlation coefficient
SD
standard deviation
TEER
transepithelial electrical resistance
TDM
tetradecylmaltoside
TDS
sodium tetradecyl sulphate
TDM
tetradodecyl maltoside
TC
taurocholate
Tpot
TEER potency
UC
Ursocholate

Keywords

Permeation enhancers
Caco-2
Random forest
QSAR
Surfactants

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