PHARMACOPHORIC PATTERN-MATCHING IN FILES OF 3-DIMENSIONAL CHEMICAL STRUCTURES - IMPLEMENTATION OF FLEXIBLE SEARCHING

The conformational space of a flexible three-dimensional (3D) molecule can be represented for searching purposes by a smoothed bounded dista nce matrix. Such matrices provide an effective way of carrying out fle xible searching, but search times can be very long when compared with rigid searches that take no account of conformational flexibility. Thi s paper considers two techniques for minimizing the computational requ irements of flexible searching. In the first part, we compare four dif ferent indices that have been suggested for the quantification of mole cular flexibility, and demonstrate that they produce comparable rankin gs of sets of molecules in order of decreasing flexibility. We then de monstrate that the prioritization of a set of structures in order of i ncreasing flexibility can result in substantial reductions in the time requirements of flexible searching if some fixed number of hit struct ures is desired. In the second part, we report an analysis of the 3D c rystal structures in the Cambridge Structural Database to generate dis tance ranges that are tighter than those produced by distance geometry . Experiments with a set of six query pharmacophores demonstrate that use of these tightened ranges results in substantial reductions in sea rch times, but that this may also lead to a reduction in the number of hit molecules obtained from the final conformational search.