Predictive model of blood-brain barrier penetration of organic compounds.
OBJECTIVE
To build up a theoretical model of organic compounds for the prediction of the activity of small molecules through the blood-brain barrier (BBB) in drug design.


METHODS
A training set of 37 structurally diverse compounds was used to construct quantitative structure-activity relationship (QSAR) models. Intermolecular and intramolecular solute descriptors were calculated using molecular mechanics, molecular dynamics simulations, quantum chemistry and so on. The QSAR models were optimized using multidimensional linear regression fitting and stepwise method. A test set of 8 compounds was evaluated using the models as part of a validation process.


RESULTS
Significant QSAR models (R=0.955, s=0.232) of the BBB penetration of organic compounds were constructed. BBB penetration was found to depend upon the polar surface area, the octanol/water partition coefficient, Balaban Index, the strength of a small molecule to combine with the membrane-water complex, and the changeability of the structure of a solute-membrane-water complex.


CONCLUSIONS
The QSAR models indicate that the distribution of organic molecules through BBB is not only influenced by organic solutes themselves, but also relates to the properties of the solute-membrane-water complex, that is, interactions of the molecule with the phospholipid-rich regions of cellular membranes.
Ma
Xiao-lei
XL
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China.
Chen
Cheng
C
Yang
Jie
J
D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D004134:Dimyristoylphosphatidylcholine; D015195:Drug Design; D008567:Membranes, Artificial; D008954:Models, Biological; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations; D004134:Dimyristoylphosphatidylcholine