HierS:  Hierarchical Scaffold Clustering Using Topological Chemical Graphs

• Published in: Journal of medicinal chemistry Vol. 48; no. 9; pp. 3182 - 3193
• Main Authors: Wilkens, Steven J, Janes, Jeff, Su, Andrew I
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05.05.2005
• Subjects: Algorithms; Aniline Compounds - chemistry; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Internet; Medical sciences; Miscellaneous; Naphthalenes - chemistry; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Pharmacology. Drug treatments; Pyrazoles - chemistry; Quantitative Structure-Activity Relationship; Cluster analysis; High throughput screening; Automation; Structure activity relation; Classification; Molecular model; Topology; Algorithm; Modeling
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049032d

An exhaustive ring-based algorithm, HierS, has been developed in order to provide an intuitive approach to compound clustering for analyzing high-throughput screening results. The recursive algorithm rapidly identifies all possible ring-delimited substructures within a set of compounds. Molecules are grouped by shared ring substructures (scaffolds) so that common scaffolds obtain higher membership. Once all of the scaffolds for a set of compounds are identified, the hierarchical structural relationships between the scaffold structures are established. The complex network of hierarchical relationships is then utilized to navigate compounds in a structurally directed fashion. When the scaffold hierarchy is traversed, over-represented structural features can be rapidly identified so that excess compounds that contain them can be removed without significantly impacting the structural diversity landscape of the compound set. Furthermore, the removed compounds can provide the opportunity to follow-up on active compounds that had previously been discarded because of practical limitations on follow-up capacity. A Web-based interface has been developed that incorporates this algorithm in order to allow for an interactive analysis. In addition, biological data are coupled to scaffolds by the inclusion of activity histograms, which indicate how the compounds in each scaffold class performed in previous high-throughput screening campaigns.