Quantifying the ability of drugs to cross the blood brain barrier

Using the CNS-MPO score to identify beneficial compounds for the treatment of neurological disease.

In a previous post I wrote about the problems and promises of antiretroviral drugs to more effectively treat brain cancer. A major challenge in using antiretroviral drugs (ART) to treat brain cancer, however exciting and novel, is getting the drugs to cross the notorious blood-brain barrier (BBB) at therapeutic doses without harming healthy cells.

To address this, we can use the CNS-MPO score, a tool that helps identify drugs that can effectively penetrate the brain. A score above 4 indicates good potential for treating neurological diseases.

I hope you can stay with me on this one. - The concept isn’t quite as daunting as it may sound, but requires a series of calculations sourced from different databases.

Articles such as the one above by Wagner et al., details how the CNS-MPO (Central Nervous System Multiparameter Optimisation) score can be used to evaluate the potential of drugs to penetrate the blood-brain barrier (BBB) and be effective in treating neurological conditions. This score helps in assessing whether a drug can reach the brain in sufficient concentrations to have a therapeutic effect.

From the meta analysis referred to in my post on ARTs as repositioned drugs to treat brain cancer, data revealed that Ritonavir (RTV) and Efavirenz (EFV) had the highest scores (RTV = 5.83; EFV = 4.12), suggesting they are good candidates. Abacavir and lamivudine did not score above 4 but can still penetrate the brain at low levels. To improve treatment, ART could be combined with other methods, like delivering drugs directly to the brain, using surgery to open the BBB, or combining with other therapies. Long-term use of multiple drugs will likely be needed to control the disease, similar to HIV treatment.

We know that in HIV, a combination of one protease inhibitor and two reverse transcriptase inhibitors has been effective in suppressing the disease. Similarly, combining ART with traditional treatments like chemoradiation has been proposed to offer a similar kind of benefit in the context of GBM to more effectively manage disease.

It would be interesting to explore combinations of non-toxic metabolic therapies as potential replacements for chemotherapy and radiation to achieve similar benefits. The CNS-MPO tool could be used to put this theory into practice by examining promising drugs with metabolic targets that do not have undesirable long- or short-term side effects.

Breaking down components of the CNS-MPO score to understand how it works

The CNS-MPO score is calculated based on several physicochemical properties of drugs. I created this graphic to illustrate what these are and there significance:

Interpreting the CNS-MPO Score:

The CNS-MPO score ranges from 0 to 6. A score above 4 is considered optimal for BBB penetration, indicating that the drug is likely to be effective for central nervous system (CNS) disorders.

This means that when selecting drugs for treating CNS conditions, it is preferable for them to score above 4 on the CNS-MPO to ensure effective penetration of the BBB. For developing specific drug cocktail protocols for brain cancer, we can compare the CNS-MPO scores of different drugs to determine which ones are more likely to be effective for neurological diseases.

Example application:

Suppose you have several antiretroviral drugs and want to determine their potential for treating glioblastoma. We have data on this from the meta-analysis on ARTs, and they are as follows:

• Ritonavir (RTV): CNS-MPO score = 5.83

• Efavirenz (EFV): CNS-MPO score = 4.12

• Abacavir (ABC): CNS-MPO score < 4

• Lamivudine (LMV): CNS-MPO score < 4

Based on these scores:

• RTV and EFV, with scores above 4, look like good candidates for CNS penetration and potentially effective for treating GBM.

• ABC and LMV, with scores below 4, may require additional strategies to improve their CNS delivery or may be less effective as standalone treatments.

How can I do this myself when scores are not provided?

There are three online tools and databases that I like to use to help determine the CNS-MPO score and other relevant properties for existing drugs. These include:

• ChEMBL: A large database of bioactive molecules with drug-like properties. It includes information on the molecular properties of compounds.

• PubChem: A free resource that provides information on the biological activities of small molecules. It includes data on molecular weight, logP, TPSA, and other properties needed for CNS-MPO score calculations. Personally I like to use this one, in conjunction with SwissADME, as my preferred databases for this task.

• SwissADME: An online tool that provides free access to a set of predictive models for evaluating the pharmacokinetics, drug-likeness, and medicinal chemistry ‘friendliness’ of small molecules. It includes calculations for logP, TPSA, and other parameters.

• Other databases - Others databases exist, but they can be confusing to the layperson and not very user friendly, so I haven’t included these.

Example of a popular repurposed drug - metformin

To provide a practical example, let’s use the SwissADME tool to calculate the relevant properties of metformin and estimate its CNS-MPO score.