Determination of in Vitro and in Silico Indexes for the Modeling of Blood–Brain Barrier Partitioning of Drugs via Micellar and Immobilized Artificial Membrane Liquid Chromatography

Russo, Giacomo; Grumetto, Lucia; Szucs, Roman; Barbato, Francesco; Lynen, Frederic

Abstract

In the present work, 79 structurally unrelated analytes were taken into account and their chromatographic retention coefficients, measured by immobilized artificial membrane liquid chromatography (IAM-LC) and by micellar liquid chromatography (MLC) employing sodium dodecyl sulfate (SDS) as surfactant, were determined. Such indexes, along with topological and physicochemical parameters calculated in silico, were subsequently used for the development of blood–brain barrier passage-predictive statistical models using partial least-squares (PLS) regression. Highly significant relationships were observed either using IAM (r2 (n – 1) = 0.78) or MLC (r2 (n – 1) = 0.83) derived indexes along with in silico descriptors. This hybrid approach proved fast and effective in the development of highly predictive BBB passage oriented models, and therefore, it can be of interest for pharmaceutical industries as a high-throughput BBB penetration oriented screening method. Finally, it shed new light into the molecular mechanism involved in the BBB uptake of therapeutics.

Citation

Russo, G., Grumetto, L., Szucs, R., Barbato, F., & Lynen, F. (2017). Determination of in Vitro and in Silico Indexes for the Modeling of Blood–Brain Barrier Partitioning of Drugs via Micellar and Immobilized Artificial Membrane Liquid Chromatography. Journal of Medicinal Chemistry, 60(9), 3739-3754. https://doi.org/10.1021/acs.jmedchem.6b01811

• Journal Article Type: Article
• Online Publication Date: Apr 27, 2017
• Publication Date: May 11, 2017
• Deposit Date: Apr 29, 2020
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 60
• Issue: 9
• Pages: 3739-3754
• DOI: https://doi.org/10.1021/acs.jmedchem.6b01811
• Keywords: Sodium dodecyl sulfate, Peptides and proteins, Chromatography, Pharmaceuticals, Screening assays
• Public URL: http://researchrepository.napier.ac.uk/Output/2655682