Development of Structure−Lipid Bilayer Permeability Relationships for Peptide-like Small Organic Molecules

Abstract

Computational methods to estimate passive membrane permeability coefficients of organic molecules, including peptides, would be valuable in understanding various biological processes associated with molecular transport across cell membranes and in reducing the time required for screening developability properties of new drug candidates. This study explores the suitability of fragment-based linear free energy relationships (LFERs) to predict lipid bilayer permeability coefficients and decadiene/water partition coefficients of a set of 47 model permeants. The inclusion of mono-, di-, and tripeptides comprised of glycine, alanine, and sarcosine residues in the database presented added challenges due to the apparent lack of independence of the contribution of the backbone amide residue in peptides to the free energy of transfer (Delta(Delta G degrees ) -CONH-) from water to organic solvents or to the bilayer barrier domain. In order to elucidate the impact of neighboring group effects on Delta(Delta G degrees ) -CONH-, a series of RGZ glycine (G)-containing peptides having an additional -NHCH 2CO- residue compared to their RZ counterparts were synthesized, where R = acetyl (Ac-), 4-carboxymethylphenyl acetyl (CMPA-), or 4-methylphenyl acetyl (MPA-), and Z = -OH, -OMe, -NHMe, or -NMe 2. While variations in R had no significant impact on Delta(Delta G degrees ) -Gly-, significant effects of neighboring ( i + 1) Z substituents at the C-terminus were revealed both in studies of the relative transport of RGZ/RZ compound pairs across DOPC bilayers and partitioning between water and 1,9-decadiene (a bulk solvent with a similar chemical selectivity to the barrier domain of DOPC/eggPC bilayers). The proximity effects decline when the bulk solvent used in partitioning studies is 1-octanol, suggesting a possible role for intramolecular hydrogen bonding in the observed nonadditivity of Delta(Delta G degrees ) -CONH-. A new LFER for predicting decadiene/water partition coefficients was developed by including the contributions of polar fragments, total nonpolar surface area of nonpolar fragments, and correction factors to account for the effects of i + 1 substituents in peptides on the group contribution of the peptide backbone amide bond to the free energy of transfer. This LFER could be used to predict lipid bilayer permeability coefficients by including an additional term to account for the added influence of molecular size on bilayer permeability.

Permeability of Fluid-Phase Phospholipid Bilayers: Assessment and Useful Correlations for Permeability Screening and Other Applications

“…Observed permeabilities generally decrease with increasing permeant MW more rapidly than in a bulk liquid. Thus, the coefficients K lip/w and D lip ⊥ are properties that reflect not only the chemical (solvent) nature of the lipid, but are also influenced by ordering of the hydrocarbon chains, 17,26,28,31,[39][40][41] as is discussed at length below. The subscript "⊥" for "perpendicular" in the symbol D lip ⊥ is significant, because-given the anisotropy of the microstructure-the lateral diffusion coefficient D lip describing motion parallel to the plane of the bilayer is generally different.…”

“…The most comprehensive data set for egg lecithin emerging from a single laboratory is that developed collectively in a series of papers by Xiang, Anderson, and coworkers, 16,17,26,28,29,[32][33][34][35]50 summarized in Table 1. It comprises four sets of compounds, namely: (1) p-toluic acid and a series of six related compounds with different chemical substitutions of a hydrogen atom on the "-methyl group, 29 (2) a corresponding series based on p-methylhippuric acid, 33 (3) a set of 15 other selected compounds, 26 and (4) a set of "peptidelike small organic molecules" studied most recently (including new peptide derivatives of p-toluic and pmethylhippuric acids).…”

“…It comprises four sets of compounds, namely: (1) p-toluic acid and a series of six related compounds with different chemical substitutions of a hydrogen atom on the "-methyl group, 29 (2) a corresponding series based on p-methylhippuric acid, 33 (3) a set of 15 other selected compounds, 26 and (4) a set of "peptidelike small organic molecules" studied most recently (including new peptide derivatives of p-toluic and pmethylhippuric acids). 28,35 The temperature applicable to all measurements is 25 • C. Of the 39 data points, 37 apply to pure egg lecithin, and two additional ones quantify the effects of 28.6 mol % cholesterol on permeability for p-methylhippuric acid and "-carbamoylp-methylhippuric acid. 17 In their data reduction, Xiang, Anderson, and coworkers treat carefully the existence of unionized and ionized forms of their weak acid solutes, which leads to pH dependence of apparent permeability coefficients, as well as mass transfer resistances associated with unstirred layers in diffusion cells.…”

“…Our model could, for example, enter a theory that relates the apparent (observed) assay permeability to the intrinsic phospholipid bilayer permeability of the neutral form of an ionizable drug. 22 Comparable in general spirit is a recent analysis by Cao et al 28 that develops a method to estimate P lip/w in egg phosphatidyldicholine (egg PC) or dioleoylphosphatidylcholine (DOPC) bilayers (regarded as equivalent), as well as 1,9-decadiene/water partition coefficients. It is formulated in terms of chemical group contributions to a total free energy, based on data for 47 selected permeant compounds.…”

“…Application of the formula to predict P lip/w from scratch requires knowledge of an appropriate lipophilicity parameter, the 1,9-decadiene/water partition coefficient identified previously by Xiang, Anderson, and coworkers. 26,[28][29][30][31][32][33][34][35] In the absence of an experimental value, this property may be estimated in terms of K oct/w together with four of the readily available Abraham solvation parameters, 36,37 as described in a companion paper. 38 Subsequent sections draw mechanistic and practical conclusions pertinent to the prediction of fluid-phase phospholipid bilayer permeability.…”