The Brain Exposure Efficiency (BEE) Score

The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration ar...

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Bibliographic Details
Published in:ACS chemical neuroscience 2020-01, Vol.11 (2), p.205-224
Main Authors: Gupta, Mayuri, Bogdanowicz, Thomas, Reed, Mark A, Barden, Christopher J, Weaver, Donald F
Format: Article
Language:English
Subjects:
Algorithms
Animals
Biological Transport - physiology
Blood-Brain Barrier
Capillary Permeability
Drug Discovery - methods
Humans
Models, Molecular
Structure-Activity Relationship
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Summary:The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration are important to neurological drug design. A novel prediction algorithm, termed the Brain Exposure Efficiency Score (BEE), is presented. BEE addresses the need to incorporate the role of trans-BBB influx and efflux active transporters by considering key brain penetrance parameters, namely, steady state unbound brain to plasma ratio of drug (K p,uu) and dose normalized unbound concentration of drug in brain (C u,b). BEE was devised using quantitative structure–activity relationships (QSARs) and molecular modeling studies on known transporter proteins and their ligands. The developed algorithms are provided as a user-friendly open source calculator to assist in optimizing a brain penetrance strategy during the early phases of small molecule molecular therapeutic design.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.9b00650