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

作者：Peter F. Ertl, Stephen P. Jelfs, Jörg R. Mühlbacher, Ansgar Schuffenhauer, Paul M. Selzer · 发表于：Journal of Medicinal Chemistry · 年份：2006 · DOI：10.1021/jm060217p · 被引用次数：255 · 研究领域：Computational Drug Discovery Methods、Synthesis and biological activity、Click Chemistry and Applications

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.