Computational and experimental evidence of blood–brain barrier permeability assessed in silico, in vitro, and in vivo

Background: To assess the efficacy of drugs used in the treatment of diseases, it is important to understand the physicochemical properties of a compound, particularly its ability to cross cellular membranes. There are many methods for determining the capacity of substances to penetrate the blood–brain barrier (BBB). The distribution of a compound between the membrane and the extracellular fluid can be expressed by a quantitative characteristic of partitioning (lipophilicity), referred to as logP, which is calculated as the ratio of the compound’s distribution between an organic phase and water.

Aim: The work aimed to determine and compare parameters that may serve as predictors of BBB penetration in silico and in vitro and to verify the obtained data in in vivo experiments.

Methods: Predictors of BBB penetration were assessed using in silico approaches (the Way2Drug portal and the VEGA ZZ software), in vitro methods based on ultraviolet spectrophotometry to determine experimental logP, and pharmacological analysis of drug effects following intraperitoneal injection using behavioral tests: open field, pole test, elevated plus maze, sexual motivation, and rotarod.

Results: Predictor values for BBB penetration were determined for 6-hydroxydopamine (6-OHDA), oxytocin, kisspeptin-10, and haloperidol (including DEEP, MEP, MLP, PSA, HBASS, HBDON, logS, logBB, logP, and others). Partition coefficients were calculated based on optical density measurements (6-OHDA, –1.01; kisspeptin-10, –0.79; oxytocin, –0.816; haloperidol, –0.2). A pharmacological evaluation of BBB penetration based on behavioral effects was performed, and theoretical (in silico) and experimental (ultraviolet spectrophotometry) partition coefficients (logPexp) were compared with in vivo pharmacological findings. The combined analyses demonstrated that only haloperidol possesses physicochemical properties favorable for BBB penetration.

Conclusions: The study has found that physicochemical properties obtained in silico and in vitro for predicting BBB penetration of drugs are confirmed by pharmacological analysis based on behavioral effects.