Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

Publisher: Bentham Science Publishers

E-ISSN: 1875-533x|25|9|1073-1089

ISSN: 0929-8673

Source: Current Medicinal Chemistry, Vol.25, Iss.9, 2018-03, pp. : 1073-1089

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Abstract

Background: Blood-brain barrier transport is an important process to be considered in drugcandidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, alsoestablishes a restrictive mechanism for the delivery of drugs into the brain. Although there are differentand complex mechanisms implicated in drug transport, in this review we focused on the prediction ofpassive diffusion through the blood-brain barrier.

Methods: We elaborated on ligand-based and structure-based models that have been described to predictthe blood-brain barrier permeability.

Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published toestablish quantitative and qualitative relationships with the blood-brain barrier permeability. We explaineddifferent types of descriptors that correlate with passive diffusion along with data analysismethods. Moreover, we discussed the applicability of other types of molecular structure-based simulations,such as molecular dynamics, and their implications in the prediction of passive diffusion. Challengesand limitations of experimental measurements of permeability and in silico predictive methodswere also described.

Conclusion: Improvements in the prediction of blood-brain barrier permeability from different typesof in silico models are crucial to optimize the process of Central Nervous System drug discovery anddevelopment.