The permeability of drug molecules through cell membranes is of outmost importance for the performance of a molecule as a drug. Unfortunately, two mechanisms for permeability, i.e. active transport and passive permeation, are competing and data with clear separation of the contributions of the mechanisms are scarce. Even more, experimental data are often derived from permeabilities through cell layers (Caco-2), which may be further contaminated by paracellular transport. This fuzzy data situation makes QSPR based prediction of biomembrane permeability difficult. In this situation, first principle prediction of biomembrane permeation would be desirable, but direct molecular mechanics approaches are essentially unfeasible due to the required system size and the time scales which have to be overcome.<br/><br/>The COSMOmic approach, which is a combination of quantum chemically derived surface polarities of solute and solvent molecules with a sound, probabilistic theory for the free energy of molecules in micellar systems, has been shown to be able to quantify the biomembrane-water partition coefficients of a wide range of drug molecules. For neutral drug compounds this was done essentially without the need of fitting any parameters to experimental biomembrane data. The extension to ionic drugs required the adjustment of the membrane potential to experimental partition coefficients by three parameters, but not to permeability data. The new method COSMOperm now combines the free energy barriers calculated with COSMOmic with a COSMO-RS based, semi-empirical prediction of diffusion coefficients of drugs in a biomembrane, resulting in a predictive model for the biomembrane permeability of neutral, acidic, basic and permanently charged compounds. One to three parameters have been adjusted to experimental data generated with the black-lipid membrane method, which does not suffer from contamination by active transport or intercellular permeation.<br/><br/>In summary, COSMOperm provides a sound and computationally efficient method to quantify the amount of passive permeation of drugs through biomembranes. Enabling an almost first principle quantification of the passive permeability may be helpful in the analysis and understanding of real-life cellular permeabilities.

Almost first principle prediction of biomembrane permeabilities with COSMOperm

256th National Meeting (2018)

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