Combined 4D-fingerprint and clustering based membrane-interaction QSAR analyses for constructing consensus Caco-2 cell permeation virtual screens.
A set of 30 structurally diverse molecules, for which Caco-2 cell permeation coefficients were determined, formed the training set for construction of Caco-2 cell permeation models based upon membrane-interaction (MI) QSAR analysis and a new QSAR method called 4D-fingerprint QSAR analysis. The descriptor terms of the 4D-fingerprints equation are molecular similarity eigenvalues, and this set of descriptors is being evaluated as a potential "universal" QSAR descriptor set. The 4D-fingerprint model suggests that Caco-2 cell permeation is governed by the spatial distribution of hydrogen bonding and nonpolar groups over the molecular shape of a molecule. Moreover, a complementary resampling of the original Caco-2 cell permeation training set, followed by the construction of several "clustered" MI-QSAR models, led to a consensus model consistent in interpretation with the 4D-fingerprint model.
Santos-Filho
Osvaldo A
OA
Division of Infectious Diseases, Faculty of Medicine, University of British Columbia, 2733 Heather Street, Vancouver, British Columbia, Canada. osvaldo@interchange.ubc.ca
Hopfinger
Anton J
AJ
D000465:Algorithms; D001185:Artificial Intelligence; D018938:Caco-2 Cells / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000502:physiology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016000:Cluster Analysis; D003198:Computer Simulation; D004134:Dimyristoylphosphatidylcholine; D004353:Drug Evaluation, Preclinical / Q000706:statistics & numerical data*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility
D004364:Pharmaceutical Preparations; D004134:Dimyristoylphosphatidylcholine