Molecular determinants of blood-brain barrier permeation

Abstract

The blood-brain barrier (BBB) is a microvascular unit which selectively regulates the permeability of drugs to the brain. With the rise in CNS drug targets and diseases, there is a need to be able to accurately predict a priori which compounds in a company database should be pursued for favorable properties. In this review, we will explore the different computational tools available today, as well as underpin these to the experimental methods used to determine BBB permeability. These include in vitro models and the in vivo models that yield the dataset we use to generate predictive models. Understanding of how these models were experimentally derived determines our accurate and predicted use for determining a balance between activity and BBB distribution.

Keywords: high-throughput; in silico; logPS; nutrient transporters; virtual screening.

Figure 1.. The blood–brain barrier is a specialized micro-vascular unit comprised of several cell types.

A major characteristic of the BBB is the presence of tight junctions between the endothelial cells, which restricts the movement of drugs via the paracellular route and forces compounds to use the transcellular routes.

Figure 2.. Schematic representation of tight junctions between endothelial cells.

Endothelial cells of the brain vasculature are sealed together by numerous tight junctions to maintain both a structural and functional role. The left panel illustrates the cell-to-cell structural relationship important for blood–brain barrier integrity. Tight junction proteins seal the surface of neighboring cells together through a complex network of both cell-to-cell extracellular interactions and intracellular anchors (center panel). Different families of tight junction proteins and their various cellular interactions have been identified; the right panel illustrates various tight junctions proteins and their intracellular and extracellular interactions in the blood–brain barrier. JAM: Junctional adhesion molecule.

Figure 3.. Relationship between the uptake of compounds in brain (PS) versus lipophilicity.

The predicted permeation of compounds into brain via passive diffusion as a function of the octanol/water partition coefficient and is illustrated by the dashed line. The actual blood–brain barrier (BBB) PS for a given compound may fall along, above or below the line of predicted PS. Compounds with measured BBB PS values close to this line gain access to brain by passive diffusion (open circles). Compounds exhibiting greater observed PS values in relation to its predicted value gain access to brain through active uptake processes (light shaded region); compounds with a lower observed PS value relative to its predicted PS value are actively restricted from brain through efflux mechanisms (darkest shaded region). PS: Permeability surface area product.

Figure 4.. Major descriptors used to calculate blood–brain barrier permeability.

This pie chart was developed by randomly looking at the major descriptors used in publications [53,59,61–77]. TPSA: Topological polar surface area.