Increasing the public activity cliff knowledge base with new categories of activity cliffs

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Activity cliffs (ACs) represent pairs of structurally similar compounds with significant differences in biological activity.
• Understanding ACs is crucial for optimizing drug candidates and predicting potential off-target effects.
• Existing knowledge bases of ACs can be expanded to include compounds with specialized structural characteristics.

Purpose of the Study:

• To extend the public knowledge base of activity cliffs (ACs) by incorporating novel categories with distinct structural features.
• To systematically identify and characterize dual-site ACs, isomer ACs, and ACs containing privileged substructures.
• To make newly identified ACs publicly available to facilitate drug discovery and development.

Main Methods:

• Development and application of systematic identification methods for novel AC categories.
• Characterization of dual-site ACs, isomer ACs, and ACs with privileged substructures.
• Data curation and public dissemination of identified ACs and their associated targets.

Main Results:

• Identification and public release of over 7400 new activity cliffs.
• These ACs exhibit activity against more than 200 different biological targets.
• The study describes novel categories including dual-site ACs, isomer ACs, and ACs with privileged substructures.

Conclusions:

• The expanded knowledge base of activity cliffs provides valuable resources for medicinal chemists and drug discovery researchers.
• Further analysis of dual-site ACs and privileged substructures will enhance the understanding of structure-activity relationships.
• Public availability of these diverse ACs promotes data sharing and accelerates the drug discovery process.