Flexible queries in 3D searching. 2. Techniques in 3D query formulation

While three-dimensional (3D) searching has emerged as a new and promising approach to computer-aided drug design, the issue of “conformational flexibility” remains an important problem. The approaches to handling this issue include considering conformational flexibility: (1) in the database itself (storage of multiple conformers); (2) in the searching procedure (on-the-fly conformational fitting); and (3) in the search queries (flexible queries). In this paper, we describe an approach using flexible queries to search for conformationally flexible molecules in a database of single 3D conformers. In addition, the utility of flexible queries in searching for commercially available chemicals as a synthetic precursor for rigid-backbone peptide mimetics is exemplified. Search results using this approach are compared with those obtained from pharmacophoric searches.