title: Predicting efflux ratios and blood-brain barrier penetration from chemical structure: combining passive permeability with active efflux by P-glycoprotein.
abstract: In order to reach their pharmacologic targets, successful central nervous system (CNS) drug candidates have to cross a complex protective barrier separating brain from the blood. Being able to predict a priori which molecules can successfully penetrate this barrier could be of significant value in CNS drug discovery. Herein we report a new computational approach that combines two mechanism-based models, for passive permeation and for active efflux by P-glycoprotein, to provide insight into the multiparameter optimization problem of designing small molecules able to access the CNS. Our results indicate that this approach is capable of distinguishing compounds with high/low efflux ratios as well as CNS+/CNS- compounds and provides advantage over estimating P-glycoprotein efflux or passive permeability alone when trying to predict these emergent properties. We also demonstrate that this method could be useful for rank-ordering chemically similar compounds and that it can provide detailed mechanistic insight into the relationship between chemical structure and efflux ratios and/or CNS penetration, offering guidance as to how compounds could be modified to improve their access into the brain.
authors: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Elena
authors: E
authors: Dolghih
authors: Matthew P
authors: MP
authors: Jacobson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001693:Biological Transport, Active / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008954:Models, Biological; D062105:Molecular Docking Simulation; D010539:Permeability
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002491:Central Nervous System Agents