PHARMACOPHORES INCORPORATING NUMEROUS EXCLUDED VOLUMES DEFINED BY X-RAY CRYSTALLOGRAPHIC STRUCTURE IN 3-DIMENSIONAL DATABASE SEARCHING - APPLICATION TO THE THYROID-HORMONE RECEPTOR

In the present study we investigate whether augmentation of pharmacoph ores with excluded (ligand-inaccessible) volumes can condense the leng thy unspecific hit lists often obtained in SD-database searching. Our pharmacophores contained hydrophobic features defined by the hormone, hydrogen bond donor and acceptor features of the liganded rat THR-alph a X-ray structure, and excluded volumes located at the positions and s caled according to the sizes of atoms delineating the binding cavity. We now show, for the first time, that it is perfectly feasible with th e Catalyst software to search, in 1-2 h, medium-sized databases such a s Maybridge (with 5 x 10(5) compounds registered as multiple conformer s) with pharmacophores containing numerous (similar to 10(2)) excluded volumes. The excluded volumes did not slow the search significantly; for pharmacophores containing more f'eatures they also reduced the siz e of the hit list the most. For example, with a 7-feature pharmacophor e, the Maybridge hit list shrank from 4 to 1. The single remaining com pound was subsequently shown to bind to THR-alpha with an IC50 of 69 m u M. Thus, we conclude that structure-based pharmacophores augmented w ith numerous excluded volumes can effectively prune and focus kit list s. The performance of multiple excluded volume-supplemented structure- based pharmacophores in 3D-database mining as implemented with the Cat alyst software compares very favorably with other published procedures , with respect to speed, specificity, and ease of use.