title: Scaffold topologies. 2. Analysis of chemical databases.
abstract: We have systematically enumerated graph representations of scaffold topologies for up to eight-ring molecules and four-valence atoms, thus providing coverage of the lower portion of the chemical space of small molecules (Pollock et al. J. Chem. Inf. Model., this issue). Here, we examine scaffold topology distributions for several databases: ChemNavigator and PubChem for commercially available chemicals, the Dictionary of Natural Products, a set of 2742 launched drugs, WOMBAT, a database of medicinal chemistry compounds, and two subsets of PubChem, "actives" and DSSTox comprising toxic substances. We also examined a virtual database of exhaustively enumerated small organic molecules, GDB (Fink et al. Angew. Chem., Int. Ed. 2005, 44, 1504-1508), and we contrast the scaffold topology distribution from these collections to the complete coverage of up to eight-ring molecules. For reasons related, perhaps, to synthetic accessibility and complexity, scaffolds exhibiting six rings or more are poorly represented. Among all collections examined, PubChem has the greatest scaffold topological diversity, whereas GDB is the most limited. More than 50% of all entries (13 000 000+ actual and 13 000 000+ virtual compounds) exhibit only eight distinct topologies, one of which is the nonscaffold topology that represents all treelike structures. However, most of the topologies are represented by a single or very small number of examples. Within topologies, we found that three-way scaffold connections (3-nodes) are much more frequent compared to four-way (4-node) connections. Fused rings have a slightly higher frequency in biologically oriented databases. Scaffold topologies can be the first step toward an efficient coarse-grained classification scheme of the molecules found in chemical databases.
authors.affiliation: Department of Mathematics and Statistics, University of New Mexico, Albuquerque, New Mexico 87131, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wester
authors.forename: Sara N
authors.initials: SN
authors.lastname: Pollock
authors.forename: Evangelos A
authors.initials: EA
authors.lastname: Coutsias
authors.forename: Tharun Kumar
authors.initials: TK
authors.lastname: Allu
authors.forename: Sorel
authors.initials: S
authors.lastname: Muresan
authors.forename: Tudor I
authors.initials: TI
authors.lastname: Oprea
mesh_terms: D002626:Chemistry, Pharmaceutical; D003628:Database Management Systems