Looking for pharmacophores in 3-D databases: Does conformational searching improve the yield of actives?

Abstract

We converted the 2-D chemical structures in the Derwent Standard Drug File database (which also contains the associated pharmacological activities) into two 3-D databases to be searched by the ChemDBS-3D module of the commercial software product Chem-X. One database was created using the Chem-X 2-D to 3-D structure converter and was keyed using ChemDBS-3D for multiple conformations per compound. The other was created using the program concord and was keyed using ChemDBS-3D for a single conformation per compound. We used ChemDBS-3D to search each database for the presence of five pharmacophores. The results were analyzed to determine whether searching a database allowing for multiple conformations per structure yields a greater fraction of compounds with the appropriate activity than searching a database with the single concord built conformation. In general, searching a database with multiple conformations yields a greater number of compounds having the the appropriate activity but with a lower percentage relative to the number of compounds found. Further, the method by which the 3-D structures were generated does affect the search effectiveness.