Title: Analysing molecular polar surface descriptors to predict blood-brain barrier permeation

Authors: Sergey Shityakov; Winfried Neuhaus; Thomas Dandekar; Carola Förster

Addresses: Department of Anesthesiology and Critical Care, University of Würzburg, 97080 Würzburg, Germany ' Department of Anesthesiology and Critical Care, University of Würzburg, 97080 Würzburg, Germany; Department of Medicinal Chemistry, University of Vienna, 1090 Vienna, Austria ' Department of Bioinformatics, University of Würzburg, 97074 Würzburg, Germany ' Department of Anesthesiology and Critical Care, University of Würzburg, 97080 Würzburg, Germany

Abstract: Molecular polar surface (PS) descriptors are very useful parameters in prediction of drug transport properties. They could be also used to investigate the blood-brain barrier (BBB) permeation rate for various chemical compounds. In this study, a dataset of drugs (n = 19) from various pharmacological groups was studied to estimate their potential properties to permeate across the BBB. Experimental logBB data were available as steady-state distribution values of the in vivo rat model for these molecules. Including accurate calculation of the electrostatic potential maps, polar surface descriptors, such as a two-dimensional polar surface area (2D-PSA), topological polar surface area (TPSA) and three-dimensional polar surface area or polar area (3D-PSA; PA) were measured and analysed. We report the strong correlation of these descriptors with logBB values for the prediction of BBB permeation using the linear partial least squares (PLS) fitting technique. The 3D-PSA descriptor showed the best fit to logBB values with R² = 0.92 and RMSD = 0.29 (p-value < 0.0001). The obtained results demonstrate that all descriptors bear high predictive powers and could provide an efficient strategy to envisage the pharmacokinetic properties of chemical compounds to permeate across the BBB at an early stage of the drug development process.

Keywords: polar surface descriptors; blood-brain barriers; BBB permeation; logBB; P-glycoprotein; drug transport properties; pharmacokinetics; chemical compounds; drug development.

DOI: 10.1504/IJCBDD.2013.052195

International Journal of Computational Biology and Drug Design, 2013 Vol.6 No.1/2, pp.146 - 156

Received: 12 May 2012
Accepted: 04 Jun 2012

Published online: 20 Feb 2013 *

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