PREDICTION OF HYDROPHOBIC (LIPOPHILIC) PROPERTIES OF SMALL ORGANIC-MOLECULES USING FRAGMENTAL METHODS - AN ANALYSIS OF ALOGP AND CLOGP METHODS

Molecular hydrophobicity (lipophilicity), usually quantified as log P (the logarithm of 1-octanol/water partition coefficient), is an import ant molecular characteristic in drug discovery. ALOGP and CLOGP are tw o of the most widely used methods for the estimation of log P. This wo rk describes an extensive reparametrization of the atomic log P values and a detailed comparison of the performance of ALOGP and CLOGP metho ds on the Pomona Medchem database. Only the ''star list'' compounds ha ving precisely measured log P values were used in this analysis. While the overall results with both methods are similar, analysis shows tha t the CLOGP method is better for very small molecules in the range of 1-20 atoms. The two methods are almost comparable in the range of 21-4 5 atoms, while the ALOGP method has better accuracy for molecules with more than 45 atoms. Although the rms deviation and the correlation co efficient for CLOGP predictions were marginally better than those for corresponding ALOGP predictions, the latter showed a very stable perfo rmance for all classes of organic compounds analyzed. The ALOGP method can be used to compute estimates of most neutral organic compounds ha ving C, H, O, N, S, Se, P, B, Si, and halogens. It also covers most zw itterionic compounds having amine and carboxylic acids and ammonium ha lide salts. The CLOGP method has improved considerably over the years to cover most neutral organic compounds, but it still has some undefin ed fragments. Finally, unlike CLOGP and other methods of predicting li pophilicity, the ALOGP method has multiple uses, such as the estimatio n of local hydrophobicity, the visualization of molecular hydrophobici ty maps, and the evaluation of hydrophobic interactions in protein-lig and complexes.