Chemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleChemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.
Publication TypeJournal Article
Year of Publication2006
AuthorsChen, I-J, Taneja, R, Yin, D, Seo, PR, Young, D, Mackerell, AD, Polli, JE
JournalMol Pharm
Volume3
Issue6
Pagination745-55
Date Published2006 Nov-Dec
ISSN1543-8384
KeywordsCaco-2 Cells, Cell Membrane Permeability, Computational Biology, Computer Simulation, Humans, Intestinal Absorption, Models, Biological, Molecular Structure, Pyridines, Quantitative Structure-Activity Relationship, Thermodynamics
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.

DOI10.1021/mp050096+
Alternate JournalMol. Pharm.
PubMed ID17140262
PubMed Central IDPMC2526287
Grant ListR01 DK067530 / DK / NIDDK NIH HHS / United States
R01 DK067530-01A1 / DK / NIDDK NIH HHS / United States
U01 FD005946 / FD / FDA HHS / United States
DK-067530 / DK / NIDDK NIH HHS / United States