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In silico prediction of unbound brain-to-plasma concentration ratio using machine learning algorithms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2011 (English)In: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, E-ISSN 1873-4243, Vol. 29, no 8, 985-995 p.Article in journal (Refereed) Published
Abstract [en]

Distribution over the blood-brain barrier (BBB) is an important parameter to consider for compounds that will be synthesized in a drug discovery project. Drugs that aim at targets in the central nervous system (CNS) must pass the BBB. In contrast, drugs that act peripherally are often optimised to minimize the risk of CNS side effects by restricting their potential to reach the brain. Historically, most prediction methods have focused on the total compound distribution between the blood plasma and the brain. However, recently it has been proposed that the unbound brain-to-plasma concentration ratio (K(p,uu,brain)) is more relevant. In the current study, quantitative K(p,uu,brain) prediction models have been built on a set of 173 in-house compounds by using various machine learning algorithms. The best model was shown to be reasonably predictive for the test set of 73 compounds (R(2) = 0.58). When used for qualitative prediction the model shows an accuracy of 0.85 (Kappa = 0.68). An additional external test set containing 111 marketed CNS active drugs was also classified with the model and 89% of these drugs were correctly predicted as having high brain exposure.

Place, publisher, year, edition, pages
2011. Vol. 29, no 8, 985-995 p.
Keyword [en]
Quantitative structure-activity relationship (QSAR), Unbound brain-to-plasma concentration ratio, Total brain-to-plasma concentration ratio, Random forest (RF), Support vector machine (SVM), Partial least squares (PLS)
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-156600DOI: 10.1016/j.jmgm.2011.04.004ISI: 000292534000002OAI: oai:DiVA.org:uu-156600DiVA: diva2:432816
Available from: 2011-08-07 Created: 2011-08-04 Last updated: 2011-08-07Bibliographically approved

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