A Computational Physics-based Approach to Predict Unbound Brain-to-Plasma Partition Coefficient, K.

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 central nervous system (CNS) drugs is characterized by a high unbound brain/plasma ratio (K). While various medicinal chemistry strategies and models have been reported to improve BBB penetration, they have limited application in predicting K directly. We describe a physics-based computational approach, a quantum mechanics (QM)-based energy of solvation (E-sol), to predict K. Prospective application of this method in internal CNS drug discovery programs highlights the utility and accuracy of this new method, which showed a categorical accuracy of 79% and an of 0.61 from a linear regression model.