Correlation and prediction of a large blood-brain distribution data set - an LFER study

Platts, James Alexis ORCID: https://orcid.org/0000-0002-1008-6595, Abraham, M. H., Zhao, Yuan H., Hersey, Anne, Ijaz, Luke and Butina, Darko 2001. Correlation and prediction of a large blood-brain distribution data set - an LFER study. European Journal of Medicinal Chemistry 36 (9) , pp. 719-730. 10.1016/S0223-5234(01)01269-7

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Abstract

We report linear free energy relation (LFER) models of the equilibrium distribution of molecules between blood and brain, as log BB values. This method relates log BB values to fundamental molecular properties, such as hydrogen bonding capability, polarity/polarisability and size. Our best model of this form covers 148 compounds, the largest set of log BB data yet used in such a model, resulting in R2=0.745 and e.s.d.=0.343 after inclusion of an indicator variable for carboxylic acids. This represents rather better accuracy than a number of previously reported models based on subsets of our data. The model also reveals the factors that affect log BB: molecular size and dispersion effects increase brain uptake, while polarity/polarisability and hydrogen-bond acidity and basicity decrease it. By splitting the full data set into several randomly selected training and test sets, we conclude that such a model can predict log BB values with an accuracy of less than 0.35 log units. The method is very rapid—log BB can be calculated from structure at a rate of 700 molecules per minute on a silicon graphics O2.

Item Type:	Article
Status:	Published
Schools:	Chemistry
Subjects:	Q Science > QD Chemistry
Uncontrolled Keywords:	blood–brain distribution; hydrogen-bonding; LFER; linear free energy relation; solute descriptors
Publisher:	Elsevier
ISSN:	0223-5234
Last Modified:	18 Oct 2022 13:08
URI:	https://orca.cardiff.ac.uk/id/eprint/12514

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