A Computational Physics-based Approach to Predict Unbound Brain-to-Plasma Partition Coefficient, Kp,uu

13 January 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The blood-brain barrier (BBB) plays a critical role in preventing harmful endogenous and exogenous substances from penetrating the brain. Optimal brain penetration of small molecule CNS drugs is characterized by a high unbound brain/plasma ratio (Kp,uu). While various medicinal chemistry strategies and in silico models have been reported to improve BBB penetration, none were developed to predict Kp,uu directly. We describe a physics-based computational approach, solvation free energy calculations (energy of solvation or E-sol), to predict Kp,uu. Prospective application of this method to internal CNS drug discovery programs highlighted the utility and accuracy of this new method, which showed a categorical accuracy of 79% and a R2 of 0.61 from a linear regression model.


brain penetration
computational chemistry
solvation free energy


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