Understanding and estimating membrane/water partition coefficients: approaches to derive quantitative structure property relationships.
In the current study we describe three approaches to derive quantitative structure property relationships (QSPRs) that give insight in the interactions that are important in membrane/water partitioning. In the first model only semiempirically (AM1) calculated descriptors are used to model membrane/water partition coefficients. Additionally, differences between the n-octanol/water and membrane/water partition coefficients are explored using a small selection of calculated descriptors. The results from both these models show that besides the partitioning between an organic phase and water, additional hydrogen-bonding parameters (epsilonLUMO, Q-, and Q+) should be taken into account. Finally, using structural fragment values, a QSPR was derived to correct the n-octanol/water partition coefficient to obtain membrane/water partition coefficients, in case that obtaining AM1 descriptors is not feasible. The QSPRs that are presented here include only alcohols, benzenes, anilines, phenols, nitrobenzenes, quinoline, esters, and amines. Due to the data limitation, the models should be regarded preliminary for other structures, and caution is necessary when modeling charged species.
Research Institute of Toxicology (RITOX), Utrecht University, P.O. Box 80176, NL-3508 TD Utrecht, The Netherlands. w.vaes@ritox.vet.uu.nl
W H
WH
Vaes
E U
EU
Ramos
H J
HJ
Verhaar
C J
CJ
Cramer
J L
JL
Hermens
D000588:Amines / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry*; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry*; D006841:Hydrocarbons, Aromatic / Q000737:chemistry; D007202:Indicators and Reagents / Q000737:chemistry*; D008956:Models, Chemical; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
D000588:Amines; D006841:Hydrocarbons, Aromatic; D007202:Indicators and Reagents; D014867:Water; D004134:Dimyristoylphosphatidylcholine