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. 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

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Free PMC article

Predicting and Improving the Membrane Permeability of Peptidic Small Molecules

Salma B Rafi et al. J Med Chem. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Plots correlating predicted and measured values for compounds 1-16. A: experimentally derived permeabilities, −logPe(A->B) and the calculated ΔGtr; B: −logPe(A->B) and the calculated value logP(oct/wat) (QikProp); C: −logPe(A->B) versus calculated hydrophilic surface area (QikProp) of each low energy conformer. Analogs bearing HBA-AA are shown in red while those without such modifications are in green. Data points are colored red for analogs with HBA-AA and green for control analogs without HBA-AA. Data points are shaped according to chemotype as follows: compounds 1-2 (square), 3-5 (circle), 6-9 (inverted triangle), 10-11 (diamond), 12-13 (triangle), 14-16 (hexagon).
Figure 2
Figure 2
A plot of predicted solubility (clogS calculated using QikProp) against the calculated ΔGtr values for the compounds 1-16. Data points are colored red for analogs with HBA-AA and green for control analogs without HBA-AA. Compound numbers are included alongside data points, which are colored and shaped as in Figure 1.

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