Second-generation activity cliffs identified on the basis of target set-dependent potency difference criteria.

Area of Science:

• Medicinal Chemistry
• Chemoinformatics
• Computational Chemistry

Background:

• Activity cliffs (ACs) represent pairs of structurally similar compounds exhibiting substantial differences in biological potency.
• ACs are valuable for elucidating structure-activity relationships (SARs), guiding drug discovery efforts.
• Current definitions of ACs rely on general similarity and potency thresholds, potentially overlooking target-specific nuances.

Purpose of the Study:

• To introduce and validate a novel, target set-dependent definition of activity cliffs.
• To analyze the formation and characteristics of these newly defined ACs.
• To enhance the relevance of activity cliffs for medicinal chemistry applications.

Main Methods:

• Assessment of activity cliffs considering target set-specific compound potency distributions.
• Development of a target set-dependent definition for activity cliffs.
• Detailed analysis of the formation mechanisms of these ACs.

Main Results:

• The study presents the first assessment of activity cliffs incorporating target set-dependent potency distributions.
• A new, target set-dependent definition of activity cliffs was established.
• Analysis revealed detailed insights into the formation of these ACs.

Conclusions:

• The proposed target set-dependent activity cliffs offer a refined perspective on SARs.
• These 'second-generation' ACs, based on target set-dependent thresholds, demonstrate increased relevance for medicinal chemistry.
• This approach provides a more nuanced understanding of how compound structure relates to activity within specific biological contexts.