ACD/Blood Brain Barrier Permeation
Predict the extent of BBB permeability, brain/plasma permeation rate, and the rate of passive diffusion from structure
The blood-brain barrier (BBB) permeation module in ACD/Percepta provides a comprehensive evaluation of the permeation potential of candidate compounds. While prediction cannot replace experimentation, this module allows compounds to be ranked according to their passive transport across the BBB.
- Predict:
- Rate of passive diffusion/permeability (logPS)
- Extent of BBB permeation (logBB)—steady-state distribution ratio of a compound between brain tissue and plasma
- Brain/plasma equilibration rate (PS * fu, brain)
Based on the last two parameters, a qualitative estimate is provided as to whether brain uptake is sufficient for CNS activity
- Receive alerts for compounds likely to undergo transport across the BBB barrier by carrier mediated mechanisms
- Improve prediction accuracy by including experimental values for logP, pKa, and fraction unbound in plasma
- Review experimental logPS or logBB values, and literature references for up to 3 similar structures from the training dataset
- View your compound on a plot of logBB vs. (PS * fu, brain), in comparison to a number of CNS and peripheral drugs
- Simplify compound screening with automated predictions for hundreds of molecules in batch mode
About the Models
Calculated Quantitative Parameters
The BBB module calculates the following quantitative characteristics of drug transport across blood-brain barrier:
- Rate of brain penetration (logPS). PS stands for Permeability-Surface area product and is defined from the kinetic equation of capillary transport (PS = -F * (1 – e-Kin/F)). By definition, PS is equal to the influx rate constant Kin corrected for blood flow rate in cerebral microcapillaries denoted as F
- Extent of brain penetration (logBB) determined by ratio of total drug concentrations in tissue and plasma at steady-state conditions (logBB = log(cbrainSS/cbloodSS)
- Fraction of drug that is unbound, i.e., pharmacologically active, in brain tissue (fu, brain)
- Brain/plasma equilibration rate given by log(PS * fu, brain)—combination of permeation rate and fraction unbound in brain, according to Liu X. et al. J Pharmacol Exp Ther., 313(3):1254–62, 2005
Data Source
The data sets used for modeling were compiled from original literature publications of BBB permeation studies in rodents. Quantitative log
PS data (determined by one of the experimental methods below) was collected for more than 250 compounds:
- Intravenous administration (IV)
- Brain uptake index (BUI)
- In situ brain perfusion
Analysis and evaluation of published brain/plasma distribution studies of drugs after intravenous, intraperitoneal, and oral administration to rats and mice yielded more than 600 log
BB values. After thorough data verification, entries supposedly affected by carrier-mediated processes were removed, leaving us with a data set of 180 log
PS and 470 log
BB values (representing BBB transport by passive diffusion).
Descriptors
Descriptors used for modeling included key physicochemical properties:
- Octanol/water logP of neutral species as a determinant of lipophilicity
- Ion form fractions at pH 7.4 calculated from the respective pKa values
- Number of hydrogen bond donors and acceptors in the molecule
- McGowan characteristic volume reflecting molecular size
Transport Mechanism Alerts
For compounds that cross the BBB by enzymatic efflux or influx, special alerts are displayed in all submodules related to the prediction of BBB transport parameters, indicating that the observed parameters for these molecules may be higher or lower than predicted values due to the presence of carrier-mediated processes, such as facilitated diffusion or P-gp efflux. Considered influx transporters include:
Amino-acid transport systems (System A, L, y+, x-)
Glucose carrier GLUT1
Organic cation/carnitine transporters (OCTN)
Organic anion transporting polypeptide (OATP)
Various other carriers specific for nucleotides and other endogenous substances
Read about the prediction accuracy of the model 
ACD/Labs Product Suites
The Percepta prediction modules are available as bundles to offer cost savings for multiple modules, and provide related modules as a package.
Contact us for more information on the product suite that is right for you.
