CAFCA: a Novel Tool for the Calculation of Amphiphilic Properties of Charged Drug Molecules

Abstract

Amphiphilic compounds play crucial roles in biology. They represent molecules with an inherent tendency to orient themselves in a suitable environment (e.g. a lipid bilayer). The driving force behind this effect is probably one of the crucial reasons for structural organization in living matter. An amphiphile typically comprises a hydrophilic as well as a hydrophobic part. The prediction of amphiphilic properties of charged small molecules by means of our in-house developed program CAFCA is presented in this work. An experimentally derived quantification of amphiphilic properties of a compound, expressed in terms of free energy of amphiphilicity (ΔΔG_AM), can be deduced from surface activity measurements. Amphiphilic moments are obtained by vector addition of individual atom/fragment contribution values. Calculated amphiphilic moments were subsequently calibrated with known free energies of amphiphilicity (ΔΔG_AM) of a homologous series of small charged amphiphiles (n-alkylsulfonic acids). The influence of conformational effects of molecules on calculated amphiphilic moments were further investigated for a set of eight structurally diverse commercially available drugs with known free energies of amphiphilicity. It turned out that conformations with maximal distance between charged group and center of gravity of the non-charged residue of the molecule yielded best results. Our calculated data and molecular modeling studies are in good accordance with experimentally derived published values. Our program CAFCA (CAlculated Free energy of amphiphilicity of small Charged Amphiphiles) can be used to estimate preferred conformations as well as orientations of molecules in biological membranes and to quantify amphiphilic properties of molecules.