Development of quantitative structure-property relationship models for early ADME evaluation in drug discovery. 2. Blood-brain barrier penetration.
A new molecular lipoaffinity descriptor was introduced in this paper to account for the effect of molecular hydrophobicity on blood-brain barrier penetration. The descriptor was defined based on Kier and Hall's atom-type electrotopological state indices. Its evaluation requires 2-D molecular bonding information only. A multiple linear regression equation using this descriptor and molecular weight reproduces the experimental logBB values of 55 training set compounds and 11 test set compounds satisfactorily with statistical parameters nearly identical to the best models based on polar surface area and ClogP. The results indicate that the lipoaffinity descriptor defined in this paper may be a significant descriptor for molecular transport properties across lipid bilayers.
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Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, USA.
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D001812:Blood-Brain Barrier; D004341:Drug Evaluation; D006860:Hydrogen Bonding; D016014:Linear Models; D008954:Models, Biological; D015394:Molecular Structure; D016571:Neural Networks, Computer; D010599:Pharmacokinetics; D021281:Quantitative Structure-Activity Relationship