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Molecular scaffolds with high propensity to form multi-target activity cliffs
1Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universitat, Dahlmannstr 2, D-53113 Bonn, Germany.
Journal of Chemical Information and Modeling
|April 6, 2010
Summary
Researchers identified 143 chemical scaffolds that frequently form activity cliffs or selectivity cliffs against multiple targets. This discovery aids in optimizing drug candidates by predicting potential promiscuity and guiding structure-activity relationship analysis.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Drug Discovery
Background:
- Activity cliffs, where structural analogs show large potency differences, are crucial in structure-activity relationship (SAR) analysis.
- Selectivity cliffs, analogous to activity cliffs, highlight analogs with differing potencies across multiple targets.
- The tendency of specific chemical scaffolds to generate activity or selectivity cliffs across various targets remains largely unexplored.
Purpose of the Study:
- To investigate whether certain chemical scaffolds exhibit a general propensity to form activity or selectivity cliffs against diverse biological targets.
- To identify and catalog scaffolds that are frequently associated with multi-target activity and selectivity cliffs.
- To provide a resource for drug discovery programs to anticipate and manage potential promiscuity in candidate compounds.
Main Methods:
- Exhaustive analysis of scaffold and compound activity data from the ChEMBL and BindingDB databases.
- Comparison of scaffold representation and target selectivity within these databases.
- Identification of scaffolds forming activity or selectivity cliffs against multiple targets.
Main Results:
- Identification of 143 scaffolds that are represented by multiple compounds and form activity or selectivity cliffs against different targets.
- Observation that these identified scaffolds vary in chemical complexity and include some promiscuous binders.
- Demonstration that analogs derived from these scaffolds can exhibit steep activity cliffs across different targets.
Conclusions:
- Certain chemical scaffolds possess an inherent tendency to yield compounds forming activity or selectivity cliffs against multiple targets.
- A catalog of high-propensity scaffolds for multi-target cliffs has been compiled, serving as a valuable tool in compound optimization.
- This resource can aid in the early identification of potentially promiscuous scaffolds during drug development efforts.
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