A 2D-QSPR approach to predict blood-brain barrier penetration of drugs acting on the central nervous system

Abstract

Drugs acting on the central nervous system (CNS) have to cross the blood-brain barrier (BBB) in order to perform their pharmacological actions. Passive BBB diffusion can be partially expressed by the blood/brain partition coefficient (logBB). As the experimental evaluation of logBB is time and cost consuming, theoretical methods such as quantitative structure-property relationships (QSPR) can be useful to predict logBB values. In this study, a 2D-QSPR approach was applied to a set of 28 drugs acting on the CNS, using the logBB property as biological data. The best QSPR model [n = 21, r = 0.94 (r² = 0.88), s = 0.28, and Q² = 0.82] presented three molecular descriptors: calculated n-octanol/water partition coefficient (ClogP), polar surface area (PSA), and polarizability (α). Six out of the seven compounds from the test set were well predicted, which corresponds to good external predictability (85.7%). These findings can be helpful to guide future approaches regarding those molecular descriptors which must be considered for estimating the logBB property, and also for predicting the BBB crossing ability for molecules structurally related to the investigated set.