CHEMICAL SIMILARITY USING GEOMETRIC ATOM PAIR DESCRIPTORS

Similarity searches using topological descriptors have proved extremel y useful in aiding large-scale screening. In this paper we describe th e geometric atom pair, the 3D analog of the topological atom pair desc riptor (Carhart et al, J. Chem. Inf. Comput. Sci. 1985, 25, 64-73). We show the results of geometric similarity searches using the CONCORD-b uild structures of typical small druglike molecules as probes. The dat abase to be searched is a 3D version of the Derwent Standard Drug File that contains an average of 10 explicit conformations per compound. U sing objective criteria for determining how good a descriptor is in se lecting active compounds from large databases, we compare the results using the geometric versus the topological atom pair. We find that geo metric and topological atom pairs are about equally effective in selec ting active compounds from large databases. How the two types of descr iptors rank active compounds is generally about the same as well, but occasionally active compounds will be seen as very similar to a probe in geometric descriptors, but as fairly dissimilar in topological desc riptors. These are of two types: (1) compounds where equivalent groups are in the same spatial arrangement as in the probe but are connected by very different bond paths and (2) compounds that can superimpose o nto the probe when they are in a folded conformation.