QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS COMPARATIVE MOLECULAR-FIELD ANALYSIS (QSAR COMFA) FOR RECEPTOR-BINDING PROPERTIES OF HALOGENATED ESTRADIOL DERIVATIVES/

The 3-D quantitative structure-activity relationships/comparative mole cular field analysis (QSAR/CoMFA) paradigm, which considers the primar y importance of the molecular fields in biological recognition, is now widely used to analyze and predict receptor-binding properties of var ious ligands. CoMFA was applied to build 3-D QSAR models of substitute d estradiol-receptor interactions, employing 3-D molecular databases o f more than 40 molecules. Ligands included the 17 alpha-ethynyl- and i someric 17 alpha(20E/Z)-(iodovinyl)estradiols and their 7 alpha-, 11 b eta-, and 12 beta-methyl (-methoxy) and -ethyl (-ethoxy) derivatives a s well as selected 2- and 4-halogenated analogs. The influence of diff erent CoMFA descriptors was studied in order to achieve the highest po ssible cross-validated gamma(2), as derived from partial least-squares calculations. Special emphasis was put on the analysis of the nature of H-bonding (donor/acceptor) interactions. The model with the best pr edictive performance (gamma(2) = 0.895) was used to visualize steric a nd electrostatic features of the QSAR (standard deviationcoefficient contour maps) and to predict receptor-binding affinities (RBA) of subs tituted estradiols other than those included in the original database. Twenty-seven test molecules were selected, including five which had p reviously been reported by other investigators. For the latter, a very good correlation with literature RBA values was obtained, which toget her with the high cross-validated gamma(2) provides evidence for the h igh predictive capacity of the model. Among the unknown structures, th e model suggests several new substitutions to derive at reasonable aff inity ligands for the estrogen receptor.