ADME evaluation in drug discovery. 4. Prediction of aqueous solubility based on atom contribution approach.

A novel method for the estimation of aqueous solubility was solely based on simple atom contribution. Each atom in a molecule has its own contribution to aqueous solubility and was developed. Altogether 76 atom types were used to classify atoms with different chemical environments. Moreover, two correction factors, including hydrophobic carbon and square of molecular weight, were used to account for the inter-/intramolecular hydrophobic interactions and bulkiness effect. The contribution coefficients of different atom types and correction factors were generated based on a multiple linear regression using a learning set consisting of 1290 organic compounds. The obtained linear regression model possesses good statistical significance with an overall correlation coefficient (r) of 0.96, a standard deviation (s) of 0.61, and an unsigned mean error (UME) of 0.48. The actual prediction potential of the model was validated through an external test set with 21 pharmaceutically and environmentally interesting compounds. For the test set, a predictive r=0.94, s=0.84, and UME=0.52 were achieved. Comparisons among eight procedures of solubility calculation for those 21 molecules demonstrate that our model bears very good accuracy and is comparable to or even better than most reported techniques based on molecular descriptors. Moreover, we compared the performance of our model to a test set of 120 molecules with a popular group contribution method developed by Klopman et al. For this test set, our model gives a very effective prediction (r=0.96, s=0.79, UME=0.57), which is obviously superior to the predicted results (r=0.96, s=0.84, UME=0.70) given by the Klopman's group contribution approach. Because of the adoption of atoms as the basic units, our addition model does not contain a "missing fragment" problem and thus may be more simple and universal than the group contribution models and can give predictions for any organic molecules. A program, drug-LOGS, had been developed to identify the occurrence of atom types and estimate the aqueous solubility of a molecule.