Quest for the Rings. In Silico Exploration of Ring Universe To Identify Novel Bioactive Heteroaromatic Scaffolds

• Published in: Journal of medicinal chemistry Vol. 49; no. 15; pp. 4568 - 4573
• Main Authors: Ertl, Peter, Jelfs, Stephen, Mühlbacher, Jörg, Schuffenhauer, Ansgar, Selzer, Paul
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27.07.2006
• Subjects: Biological and medical sciences; Biological Availability; Databases, Factual; Drug Design; Heterocyclic Compounds - chemistry; Hydrocarbons, Aromatic - chemistry; Medical sciences; Miscellaneous; Molecular Structure; Neural Networks (Computer); Pharmaceutical Preparations - chemistry; Pharmacology. Drug treatments; Quantum Theory; Drug; Prediction; Virtual screening; Neural network; Tricyclic compound; Modeling; Research and development; Self organization; Structure activity relation; Chemical compound library; Molecular model; Aromatic compound; Chemometrics; Heterocyclic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060217p

Bioactive molecules only contain a relatively limited number of unique ring types. To identify those ring properties and structural characteristics that are necessary for biological activity, a large virtual library of nearly 600 000 heteroaromatic scaffolds was created and characterized by calculated properties, including structural features, bioavailability descriptors, and quantum chemical parameters. A self-organizing neural network was used to cluster these scaffolds and to identify properties that best characterize bioactive ring systems. The analysis shows that bioactivity is very sparsely distributed within the scaffold property and structural space, forming only several relatively small, well-defined “bioactivity islands”. Various possible applications of a large database of rings with calculated properties and bioactivity scores in the drug design and discovery process are discussed, including virtual screening, support for the design of combinatorial libraries, bioisosteric design, and scaffold hopping.