Biomimetic Chromatographic Studies Combined with the Computational Approach to Investigate the Ability of Triterpenoid Saponins of Plant Origin to Cross the Blood–Brain Barrier

Katarzyna Stępnik

doi:10.3390/ijms22073573

Abstract

Biomimetic (non-cell based in vitro) and computational (in silico) studies are commonly used as screening tests in laboratory practice in the first stages of an experiment on biologically active compounds (potential drugs) and constitute an important step in the research on the drug design process. The main aim of this study was to evaluate the ability of triterpenoid saponins of plant origin to cross the blood–brain barrier (BBB) using both computational methods, including QSAR methodology, and biomimetic chromatographic methods, i.e., High Performance Liquid Chromatography (HPLC) with Immobilized Artificial Membrane (IAM) and cholesterol (CHOL) stationary phases, as well as Bio-partitioning Micellar Chromatography (BMC). The tested compounds were as follows: arjunic acid (Terminalia arjuna), akebia saponin D (Akebia quinata), bacoside A (Bacopa monnieri) and platycodin D (Platycodon grandiflorum). The pharmacokinetic BBB parameters calculated in silico show that three of the four substances, i.e., arjunic acid, akebia saponin D, and bacoside A exhibit similar values of brain/plasma equilibration rate expressed as logPSFubrain (the average logPSFubrain: −5.03), whereas the logPSFubrain value for platycodin D is –9.0. Platycodin D also shows the highest value of the unbound fraction in the brain obtained using the examined compounds (0.98). In these studies, it was found out for the first time that the logarithm of the analyte–micelle association constant (logKMA) calculated based on Foley’s equation can describe the passage of substances through the BBB. The most similar logBB values were obtained for hydrophilic platycodin D, applying both biomimetic and computational methods. All of the obtained logBB values and physicochemical parameters of the molecule indicate that platycodin D does not cross the BBB (the average logBB: −1.681), even though the in silico estimated value of the fraction unbound in plasma is relatively high (0.52). As far as it is known, this is the first paper that shows the applicability of biomimetic chromatographic methods in predicting the penetration of triterpenoid saponins through the BBB.

Highlights

Neurodegenerative related diseases constitute a growing health issue in aging populations worldwide
The main aim of the study was to evaluate the ability of naturally occurring triterpenoid saponins to cross the blood–brain barrier based on both computational analyses including Quantitative Structure-Activity Relationship (QSAR) methodology and biomimetic studies using adequate liquid chromatographic techniques
Based on the studies presented in this paper, it is largely probable that the other three saponins, i.e., arjunic acid, akebia saponin D, and bacoside A, can penetrate the blood–brain barrier (BBB)

Summary

Introduction

Neurodegenerative related diseases constitute a growing health issue in aging populations worldwide. The need for high-throughput screening has increased dramatically over the past several decades as a result of constant pressure on pharmaceutical companies to accelerate drug discovery while reducing drug development costs [3]. In this aspect, an important role is played by the biomimetic (non-cell based in vitro) and computational (in silico) methods which have been developed and improved in recent years for the prediction of compound ADME properties (absorption, distribution, metabolism, excretion) [6,7]

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Conclusion