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J Med Chem. 2012 Apr 12;55(7):3163-9. doi: 10.1021/jm201634q. Epub 2012 Mar 20.

Predicting and improving the membrane permeability of peptidic small molecules.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.

Abstract

We evaluate experimentally and computationally the membrane permeability of matched sets of peptidic small molecules bearing natural or bioisosteric unnatural amino acids. We find that the intentional introduction of hydrogen bond acceptor-donor pairs in such molecules can improve membrane permeability while retaining or improving other favorable drug-like properties. We employ an all-atom force field based method to calculate changes in free energy associated with the transfer of the peptidic molecules from water to membrane. This computational method correctly predicts rank order experimental permeability trends within congeneric series and is much more predictive than calculations (e.g., clogP) that do not consider three-dimensional conformation.

PMID:
22394492
PMCID:
PMC3325374
DOI:
10.1021/jm201634q
[Indexed for MEDLINE]
Free PMC Article

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