Computational model for predicting chemical substituent effects on passive drug permeability across parallel artificial membranes.

Molecular Pharmaceutics
Chayan AcharyaAlexander D MacKerell

Abstract

Drug permeability is often a limiting step in drug action, requiring chemical optimization of a drug candidate to improve this property. Such optimization is typically performed in the context of a congeneric series, where substituents are varied to optimize the target property. Motivated by this need the present work examines the influence of chemical substituents on passive permeability (log P pass) across parallel artificial membranes (PAMPA) undertaken for three congeneric series of compounds; benzoic acids, pyridines and quinolines. PAMPA showed pyridine and quinoline to have high permeability and chemical substituents to typically reduce the permeability. On the contrary, benzoic acid showed poor permeability and chemical substituents typically increased the permeability. To quantitate these effects with respect to physical properties, models were built to explain and predict the permeability of these classes of compounds based on computed molecular descriptors. Models for the benzoic acid series in the ionized state indicated the solvent accessible surface area, cavity dispersion and the free energy of solvation in hexane as well as in water to dominate permeability. However, when the acid group is treated as neutral, th...Continue Reading

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Citations

Oct 30, 2012·Journal of Molecular Modeling·Fancui Meng, Weiren Xu
Mar 8, 2012·Journal of Medicinal Chemistry·Salma B RafiAdam R Renslo
Jun 19, 2010·Molecular Pharmaceutics·Christopher W CunninghamJeffrey P Krise
Aug 2, 2014·European Journal of Medicinal Chemistry·Kylie A MacGregorAdam McCluskey

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