Log D versus HPLC derived hydrophobicity: The development of predictive tools to aid in the rational design of bioactive peptoids

Abstract

Hydrophobicity has proven to be an extremely useful parameter in small molecule drug discovery programmes given that it can be used as a predictive tool to enable rational design. For larger molecules, including peptoids, where folding is possible, the situation is more complicated and the average hydrophobicity (as determined by RP‐HPLC retention time) may not always provide an effective predictive tool for rational design. Herein, we report the first ever application of partitioning experiments to determine the log D values for a series of peptoids. By comparing log D and average hydrophobicities we highlight the potential advantage of employing the former as a predictive tool in the rational design of biologically active peptoids.

Peptide/β-Peptoid Hybrids with Ultrashort PEG-Like Moieties: Effects on Hydrophobicity, Antibacterial Activity and Hemolytic Properties

“…To investigate the effect of sPEGs attached at the termini or inserted at various positions within the sequence, these moieties were introduced via commercially available amino acids containing varying repeats (n times) of oxyethylene units (i.e., sPEGn; Figure 1). highly cationic peptides and peptidomimetics [17,36,[41][42][43][44]. Recently, within a large set of peptidomimetics, resembling those in the present study, we identified a correlation between hydrophobicity (expressed as percent acetonitrile at peak elution in analytical RP-HPLC) and both antibacterial activity and hemolytic properties [17].…”

“…While partition coefficients, e.g., log D values, are typically utilized in the estimation of the hydrophobicity of small molecules, the relative retention in reverse-phase HPLC (RP-HPLC) represents a more appropriate measure of hydrophobicity for very polar and highly cationic peptides and peptidomimetics [17,36,[41][42][43][44]. Recently, within a large set of peptidomimetics, resembling those in the present study, we identified a correlation between hydrophobicity (expressed as percent acetonitrile at peak elution in analytical RP-HPLC) and both antibacterial activity and hemolytic properties [17].…”

Heterochirality and Halogenation Control Phe-Phe Hierarchical Assembly

“…All compounds 1 – 6 formed supramolecular hydrogels as confirmed by oscillatory rheology (see Supporting Information , Section S8). The minimum gelling concentration (mgc) was inversely proportional to the HPLC retention time, which is an experimental measure of hydrophobicity, 37 as shown in Table 1 . However, not all hydrogels were stable over time ( Figure 1 ).…”

Supramolecular hydrogels from unprotected dipeptides: a comparative study on stereoisomers and structural isomers

“…Overall, from the rheological analysis, we inferred that heterochirality promoted hydrogelation, since in the case of Leu-Phe, it reduced gelation time, while in the case of Phe-Leu, it yielded a gel in contrast to the non-gelling L-isomer. The reasons behind this phenomenon could lie in the hydrophobicity increase, as supported by HPLC retention times (Rt), 33 which were higher for heterochiral than homochiral isomers (Table 1). It was recently demonstrated on hydrophobic tripeptides that heterochirality oriented the side chains on the same side of the peptide backbone, contrarily to the L-isomers.…”