Membrane Permeability

Physics-based, accurate predictions of passive membrane permeability

The Advantage of a Physics-based Model

Unlike QSAR-based modeling, physics-based models offer more robustness across diverse chemistries, due to the models’ ability to address conformation dependent phenomena such as internal hydrogen-bonding, which can have a dramatic effect on permeability but cannot be accurately modeled by QSAR approaches.

Macrocycle support:
Automatic detection and sampling of macrocycles via Prime’s advanced macrocycle sampling algorithm.

Partition energy “dG” Insert prediction:
Purely physics-based model, excellent for congeneric datasets.

RRCK cell-based assay Papp prediction:
Physics-based model tuned to predict RRCK (MDCK-LE) assay logPapp values.

Citations and Acknowledgements

Schrödinger Release 2017-2: Prime, Schrödinger, LLC, New York, NY, 2017.

ö Leung, S. S. F., Sindhikara, D. J., and Jacobson, M. P., "Simple Predictive Models of Passive Membrane Permeability Incorporating Size-Dependent Membrane-Water Partition," J. Chem. Inf. Model., 2016, 56(5), 924–929

ö Leung, S.S.F, Mijalkovic, J., Borrelli, K., and Jacobson, M.P., "Testing Physical Models of Passive Membrane Permeation," J. Chem. Inf. Model., 2012, 52(6), 1621-1636

ö Rezai, T., Yu, B., Millhauser, G.L., Jacobson, M.P., and, and Lokey, R.S., "Testing the Conformational Hypothesis of Passive Membrane Permeability Using Synthetic Cyclic Peptide Diastereomers," J. Am. Chem. Soc. Model., 2006, 128(8), 2510–2511

ö "Simple Predictive Models of Passive Membrane Permeability Incorporating Size-Dependent Membrane-Water Partition"

Leung, S. S. F., Sindhikara, D. J., and Jacobson, M. P., J. Chem. Inf. Model., 2016, 56(5), 924–929

"Predicting and improving the membrane permeability of peptidic small molecules"

Rafi, S.B.; Hearn, B.R.; Vedantham, P.; Jacobson, M.P.; Renslo, A.R., J. Med. Chem., 2012, 55(7), 3163-3169

ö "Testing physical models of passive membrane permeation"

Leung, S.S.F.; Mijalkovic, J.; Borrelli, K.; Jacobson, M.P., J. Chem. Inf. Model., 2012, 52(6), 1621-1636

"Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: Successful in silico prediction of the relative permeabilities of cyclic peptides"

Rezai, T.; Bock, J. E.; Vong, M.; Lokey, R. S.; Jacobson, M. P., J. Am. Chem. Soc, 2006, 128, 14073-14080

"Testing the Conformational Hypothesis of Passive Membrane Permeability Using Synthetic Cyclic Peptide Diastereomers"

Rezai, T., Yu, B., Millhauser, G.L., Jacobson, M.P., and, and Lokey, R.S., J. Am. Chem. Soc. Model., 2006, 128(8), 2510–2511
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