Multidimensional screening and design of pharmaceuticals by using endocrine pharmacophores

A novel computational technology derived from gene structure has been devel oped for screening, selecting, and designing pharmaceutical candidates. Pha rmacophores, or three-dimensional molecular blueprints, were created by doc king known active structures into specific sites in partially unwound DNA. The pharmacophores are composites of the van der Waals surfaces and hydroge n bonding functional groups of active molecules. Once created, molecules ca n be inserted into the pharmacophores and degree of fit quantitated by the volume of the molecule that fits within the composite surface and the magni tude of electrostatic interactions with charged atoms on the pharmacophore. Here, we describe endocrine pharmacophores and in particular the estrogen pharmacophore derived by docking active ligands into partially unwound DNA. Fit of candidate structures into the estrogen pharmacophore correlated wit h estrogenic (uterotropic) activity. For example, the super active estrogen s moxestrol and 11 beta-acetoxyestradiol fit better within the site than es tradiol. Bisphenol A, a putative endocrine disrupter with suspected estroge nic activity, was a poor fit in the pharmacophore. Consistent with this pre diction, bisphenol A was recently shown to lack uterotropic activity, The c apacity of the endocrine pharmacophores to predict certain nontarget activi ties was demonstrated by using the antiandrogen cyproterone acetate that di d not fit the estrogen or thyroid pharmacophores but fit partially into the progestin and glucocorticoid pharmacophores. Cyproterone acetate: has been reported to have weak progestational and glucocorticoid activities, The ph armacophores provide for the first time a multidimensional computational me thod that can simultaneously predict multiple activities of diverse molecul ar structures, (C) 1999 Published by Elsevier Science inc. All rights reser ved.