title: Chemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.
abstract: The objective was (1) to evaluate the chemical substituent effect on Caco-2 permeability, using a congeneric series of pyridines, and (2) compare molecular descriptors from a computational chemistry approach against molecular descriptors from the Hansch approach for their abilities to explain the chemical substituent effect on pyridine permeability. The passive permeability of parent pyridine and 14 monosubstituted pyridines were measured across Caco-2 monolayers. Computational chemistry analysis was used to obtain the following molecular descriptions: solvation free energies, solvent accessible surface area, polar surface area, and cavitation energy. Results indicate that the parent pyridine was highly permeable and that chemical substitution was able to reduce pyridine permeability almost 20-fold. The substituent effect on permeability provided the following rank order: 3-COO- < 4-NH2 < 3-CONH2 < 3-Cl < 3-CHO < 3-OH < 3-CH2OH < 3-C6H5 < 3-NH2 < 3-CH2C6H5 < 3-C2H5 < 3-H < 3-CH3 < 3-F < 4-C6H5. This substituent effect was better explained via molecule descriptors from the computational chemistry approach than explained by classic descriptors from Hansch. Computational descriptors indicate that aqueous desolvation, but not membrane partitioning per se, dictated substituent effect on permeability.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
authors.forename: I-Jen
authors.initials: IJ
authors.lastname: Chen
authors.forename: Rajneesh
authors.initials: R
authors.lastname: Taneja
authors.forename: Daxu
authors.initials: D
authors.lastname: Yin
authors.forename: Paul R
authors.initials: PR
authors.lastname: Seo
authors.forename: David
authors.initials: D
authors.lastname: Young
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D008954:Models, Biological; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics*; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D011725:Pyridines; C023666:pyridine