Analyzing Molecular Polar Surface Descriptors to Predict Blood-Brain Barrier Permeation
Poster Apr 23, 2012
Sergey Shityakova, Winfried Neuhausa, Thomas Dandekarc and Carola Förstera
Permeation of active drugs across the vascular brain endothelium into the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). The BBB separates the bloodstream from the brain. Characteristics of the BBB are the restriction of paracellular substance permeation across the endothelium by intercellular tight junctions, the lack of cellular fenestrae and reduced pinocytosis (van Bree et al., 1992). In contrast to several endogenous hydrophilic nutrients (glucose, amino acids, etc...), which are transported by carrier-mediated mechanisms across the brain endothelium, the BBB prevents the entry into the CNS of the majority of polar drugs (Geldenhuys et al., 2010).
Some molecular quantities like polar surface (PS) descriptors are of key interest to medicinal chemists to predict the BBB permeation fate for different drug-like chemical compounds. The descriptors commonly used to account for polarity are the so-called polar surface descriptors, such as two-dimensional polar surface area (2D-PSA), topological polar surface area (TPSA) and three-dimensional polar surface area or polar area (3D-PSA, PA) (Kelder et al., 1999). The last has to be calculated with time consuming quantum-mechanical methods usually providing better results.
We report the prediction of the BBB permeation by analyzing polar surface descriptors of various CNS-active/inactive compounds to find a strong correlation of these descriptors with logBB values using the linear partial least squares (PLS) fitting technique. In the case of effective CNS- acting drugs, the understanding of permeation mechanism through the BBB is pivotal to filter potential leads and to estimate and diminish the various neurotoxic side-effects.