Testing Physical Models of Passive Membrane Permeation

The biophysical basis of passive membrane permeability is well-understood, but most methods for predicting membrane permeability in the context of drug design are based on statistical relationships that indirectly capture the key physical aspects. Here, we investigate molecular mechanics-based model...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2012-06, Vol.52 (6), p.1621-1636
Main Authors: Leung, Siegfried S. F, Mijalkovic, Jona, Borrelli, Kenneth, Jacobson, Matthew P
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biophysics
Cell Line
Diffusion
Drug Design
General pharmacology
Humans
Medical sciences
Membranes
Models, Theoretical
Molecular chemistry
Performance evaluation
Permeability
Pharmaceutical technology. Pharmaceutical industry
Pharmacokinetics
Pharmacology
Pharmacology. Drug treatments
Quantitative Structure-Activity Relationship
Thermodynamics
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Summary:The biophysical basis of passive membrane permeability is well-understood, but most methods for predicting membrane permeability in the context of drug design are based on statistical relationships that indirectly capture the key physical aspects. Here, we investigate molecular mechanics-based models of passive membrane permeability and evaluate their performance against different types of experimental data, including parallel artificial membrane permeability assays (PAMPA), cell-based assays, in vivo measurements, and other in silico predictions. The experimental data sets we use in these tests are diverse, including peptidomimetics, congeneric series, and diverse FDA approved drugs. The physical models are not specifically trained for any of these data sets; rather, input parameters are based on standard molecular mechanics force fields, such as partial charges, and an implicit solvent model. A systematic approach is taken to analyze the contribution from each component in the physics-based permeability model. A primary factor in determining rates of passive membrane permeation is the conformation-dependent free energy of desolvating the molecule, and this measure alone provides good agreement with experimental permeability measurements in many cases. Other factors that improve agreement with experimental data include deionization and estimates of entropy losses of the ligand and the membrane, which lead to size-dependence of the permeation rate.
ISSN:1549-9596
1549-960X
DOI:10.1021/ci200583t