Prediction of blood-brain partitioning and human serum albumin binding based on COSMO-RS sigma-moments.

Models for the prediction of blood-brain partitioning (logBB) and human serum albumin binding (logK(HSA)) of neutral molecules were developed using the set of 5 COSMO-RS sigma-moments as descriptors. These sigma-moments have already been introduced earlier as a general descriptor set for partition coefficients. They are obtained from quantum chemical calculations using the continuum solvation model COSMO and a subsequent statistical decomposition of the resulting polarization charge densities. The model for blood-brain partitioning was built on a data set of 103 compounds and yielded a correlation coefficient of r2 = 0.71 and an rms error of 0.40 log units. The human serum albumin binding model was built on a data set of 92 compounds and achieved an r2 of 0.67 and an rms error of 0.33 log units. Both models were validated by leave-one-out cross-validation tests, which resulted in q2 = 0.68 and a qms error of 0.42 for the logBB model and in q2 = 0.63 and a qms error of 0.35 for the logK(HSA) model. Together with the previously published models for intestinal absorption and for drug solubility the presented two models complete the COSMO-RS based set of ADME prediction models.