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

Abstract

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 p,uu ). While various medicinal chemistry strategies and in silico models have been reported to improve BBB penetration, they have limited application in predicting K p,uu directly. We describe a physics-based computational approach, a quantum mechanics (QM)-based energy of solvation (E-sol), to predict K p,uu . 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 R 2 of 0.61 from a linear regression model.

Accurate prediction of Kp,uu,brain based on experimental measurement of Kp,brain and computed physicochemical properties of candidate compounds in CNS drug discovery

“… A categorical accuracy of 79 % and an R 2 of 0.61 from a linear regression model. [ 18 ]/2023 Mathematical equation model: Training set: 226 compounds Internal test set: 30 compounds External test: 36 literature compounds. ANN model: Training set: 262 compounds Test set: 30 compounds K p,brain : mice, single timepoint f u,b and f u,p : equilibrium dialysis Mathematical equation model using experimental K p,brain , and in silico predicted ratio of f u,b /f u,b.…”

“…Multiple in silico models for the prediction of K p,brain or K p,uu,brain that were built on different datasets have been reported in recent years [ [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] ], but the results were not satisfactory. The development of K p,uu,brain models is inherently challenging because they must account for the roles of all membrane transporters at the BBB [ 19 ].…”

Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules

“…The lack of experimental data for Kp,uu has also limited the development of highly accurate in silico prediction models of Kp,uu. Only a few in silico models of Kp,uu with moderate accuracy have been reported [ 23 , 36 , 37 , 38 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Poor performance of global models of Kp,uu is understandable as (a) the training datasets do not have good coverage of chemical space, and (b) models need to account for multiple factors that affect brain penetration, e.g., experimental protocols and animal species, as explained above.…”

“…Zhang et al [ 82 ] developed a binary Kp,uu classification model on a dataset containing 677 and 169 molecules in training and test sets, respectively, which showed similar accuracy (R 2 ~0.75). Lawrenz et al [ 83 ] proposed a physics-based approach to predict Kp,uu using solvation energy from quantum mechanical calculations.…”

CNSMolGen: A Bidirectional Recurrent Neural Network-Based Generative Model for De Novo Central Nervous System Drug Design

“…Along with the social construction of population aging, the incidence of CNS disorders, including Alzheimer disease (AD), Parkinson’s disease (PD), and depression, is continuously increasing . However, the number of approved drugs targeting these diseases remains limited, partially attributed to the blood–brain barrier (BBB) that prevents the access of drug molecules into the CNS. , Consequently, the discovery and development of novel and effective drugs for the treatment of human CNS disorders remains a crucial responsibility in the field of pharmaceutical sciences. , …”