Structure-property model for membrane partitioning of oligopeptides

The aim of this study was to develop a structure-property model for membran e partitioning of oligopeptides using statistical design methods and multiv ariate data analysis. A set of 20 tetrapeptides with optional N-methylation s at residues 2 and 4 was designed by a D-optimal design procedure. After s ynthesis and purification, the membrane partitioning abilities of the pepti des were tested in two chromatographic systems with phospholipids as the st ationary phase: immobilized artificial membrane chromatography (IAM) and im mobilized liposome chromatography (ILC). The relationship between these mea sures and three different sets of calculated descriptors was analyzed by pa rtial least-squares projection to latent structures (PLS). The descriptors used were the molecular surface area, Molsurf parameters, and Volsurf param eters. All three models were of good statistical quality and supported that a large hydrogen-bonding potential and the presence of a negative charge i mpair membrane partitioning, whereas hydrophobic parameters promote partiti oning. The findings are in accordance with what has been found for absorpti on of known drugs and have implications for the design of peptide-like drug s with good oral bioavailability.