Blood-Brain Barrier (BBB) Score Predictor

The following manual gives you a walk-through on how to use the BBB Score Predictor.

Table of Contents

• Introduction
• Availability
  • MarvinSketch
  • cxcalc
  • Chemical Terms
  • API
• Accuracy report
• Licensing
• References

Introduction

The blood-brain barrier (BBB) is a crucial part of the human central nervous system (CNS). It is a cell layer functioning as a protective barrier for the brain against possible pathogenic organisms. It also regulates the transport of different molecules into the brain, including nutrients necessary for neural function, ions and drugs.

This barrier plays an important role in the design of drugs because CNS-targeted compounds should cross the BBB to reach a certain therapeutic level in the brain tissue. However, high levels of non-CNS drugs appearing in the brain can cause unwanted side effects, making the BBB penetration a distinctive feature for CNS targeting.

To understand the BBB penetration of drugs, Gupta et al. studied their physico-chemical property spaces and developed a score (called BBB Score) to predict if a drug is preferentially CNS or non-CNS active.

The BBB Score is composed of 5 physico-chemical descriptors: the number of aromatic rings, the number of heavy atoms, MWHBN (a descriptor calculated from the molecular weight and the number of H-bond donor and acceptor atoms), the topological polar surface area (TPSA) and the pKa. The final score is calculated using stepwise (for descriptors with purely discrete values) and polynomial weight functions (for descriptors having continuous ranges).

The research revealed that (tested on a set of 270 CNS and 720 non-CNS drugs) the BBB Score (a number between 0 and 6) is a distinctive predictor of CNS drug-likeness. Molecules with BBB Scores between 0 and less than 4 can be classified as non-CNS drugs, while molecules with BBB Scores between 4 and 6 can be classified as CNS drugs.

Chemaxon's BBB Score Predictor is able to predict the BBB Score based on the formula published by Gupta et al.

Availability

The BBB Score prediction has been available since v. 22.21 in the following Chemaxon products.

MarvinSketch

In MarvinSketch the BBB Score prediction is available under the Calculations » Other » BBB score menu item.

cxcalc

Use the bbb function to predict the BBB Score with cxcalc:

cxcalc -N ih bbb sildenafil
3.05

From v. 24.1 the properties and their contributions to the BBB Score can also be returned with the -c option:

cxcalc -N i bbb -c true sildenafil  
BBB score    ARO_R    HA    MWHBN    TPSA    PKA    ARO_R_SCORE    HA_SCORE    MWHBN_SCORE    TPSA_SCORE    PKA_SCORE
3.05    3.00    33.00    0.37    109.13    6.59    0.69    0.61    0.60    0.24    0.73

Chemical Terms

Use the bbb() function to predict the BBB Score with Chemical Terms:

evaluate -e "bbb()" sildenafil
3.05

From v. 24.1 the properties and their contributions to the BBB Score can also be returned. For example:

evaluate -e "bbb('PKA')" sildenafil
6.59

evaluate -e "bbb('PKA_SCORE')" sildenafil
0.73

API

The BBB Score prediction is also available via the public Java API and the Calculations Web Services API.

Accuracy report

We tested the BBB Score Predictor on a test set of 269 molecules available in the reference. The table below shows the number of test molecules for which the predicted BBB Score falls within the delta range of 0-0.5 and 0.5-1.0, respectively.

Range	Number of compounds (269 in total)
0.0-0.5	267
0.5-1.0	2

Licensing

From v. 24.1 the BBB Score prediction requires an ADMET license. However, Protonation and Structural Calculations licenses are required to get the BBB Score properties and their contributions. Please see details here.

 **_NOTE:_** Predicting the BBB Score in MarvinSketch requires ONLY the MarvinBeans license. In other Chemaxon tools it requires the mentioned licenses above.

References

1. Gupta, Mayuri et al. (2019). The Blood-Brain Barrier (BBB) Score, J. Med. Chem. 2019, 62(21), 9824–9836.

https://doi.org/10.1021/acs.jmedchem.9b01220