Journal
MOLECULAR INFORMATICS
Volume 31, Issue 11-12, Pages 837-846Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/minf.201200078
Keywords
Activity cliffs; Activity landscape; Cheminformatics; Molecular similarity; PPAR Agonist; Structure-activity similarity (SAS) maps; Structure-activity relationships
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Funding
- CONACyT [80093, 245408]
- State of Florida, Executive Office of the Governor's Office of Tourism, Trade, and Economic Development
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Structure-activity relationships (SAR) of compound databases play a key role in hit identification and lead optimization. In particular, activity cliffs, defined as a pair of structurally similar molecules that present large changes in potency, provide valuable SAR information. Herein, we introduce the concept of activity cliff generator, defined as a molecular structure that has a high probability to form activity cliffs with molecules tested in the same biological assay. To illustrate this concept, we discuss a case study where Structure-Activity Similarity maps were used to systematically identify and analyze activity cliff generators present in a dataset of 168 compounds tested against three peroxisome-proliferator-activated receptor (PPAR) subtypes. Single-target and dual-target activity cliff generators for PPARa and d were identified. In addition, docking calculations of compounds that were classified as cliff generators helped to suggest a hot spot in the target protein responsible of activity cliffs and to analyze its implication in ligand-enzyme interaction.
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