ASSESSMENT OF METHODS USED FOR PREDICTING LIPOPHILICITY - APPLICATIONTO NUCLEOSIDES AND NUCLEOSIDE BASES

Estimating log P (logarithm of ''1-octanol to water'' partition coeffi cients) as a measure of lipophilicity for organic compounds is of cons iderable importance in drug discovery. Several methods have been devel oped for this purpose, each with its own drawbacks and advantages. In this article, a systematic comparison of three well-documented and ful ly computerized methods has been attempted for a set of nucleosides an d bases. The first method (BLOGP) is based on overall molecular proper ties derived from a molecular orbital calculation to predict log P. Th e second method (CLOGP) uses fragmental lipophilicity constants with c orrection factors and treats log P as an additive-constitutive propert y. The third method (ALOGP) is based on an additivity scheme of atomic lipophilicity constants, with the constitutive factor governed by an elaborate list of atom types. However, none of these methods take into account conformational flexibility or intramolecular hydrogen bonding , which can cause substantial discrepancy between observations and pre dictions. A comparison of predictions from each of these methods indic ates that the atomic contribution method (ALOGP with r = 0.842 and SD = 0.51) is better than other methods (with r = 0.395 and SD = 1.2 for BLOGP and r = 0.713 and SD = 0.93 for CLOGP) for this class of compoun ds. Our overall assessment is that we do not have, as yet, a highly re liable, fully computerized log P prediction method applicable to flexi ble heterocycles such as nucleoside analogs. (C) 1993 by John Wiley & Sons. Inc.