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Do medicinal chemists learn from activity cliffs? A systematic evaluation of cliff progression in evolving compound
Dilyana Dimova1, Kathrin Heikamp, Dagmar Stumpfe
1Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität , Dahlmannstrasse 2, D-53113 Bonn, Germany.
Journal of Medicinal Chemistry
|March 27, 2013
Summary
Medicinal chemists often overlook activity cliffs, which are pairs of similar compounds with large potency differences. Further exploration of these unexplored cliffs could unlock significant opportunities for drug discovery and optimization.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Structure-Activity Relationship (SAR) studies
Background:
- Activity cliffs, defined as structurally similar compounds with significant potency differences, offer high SAR information content.
- These cliffs are valuable for SAR exploration and compound optimization in drug development.
- The extent of activity cliff utilization in practical medicinal chemistry remains largely unknown.
Purpose of the Study:
- To investigate the extent to which activity cliff information is utilized in medicinal chemistry.
- To identify opportunities for further chemical exploration and potency improvement based on activity cliffs.
Main Methods:
- Assembled 56 compound data sets that evolved over time.
- Searched for analogues of activity cliff-forming compounds with increased potency.
- Analyzed data to determine the frequency of further chemical exploration and potency progression for identified activity cliffs.
Main Results:
- Approximately 75% of all analyzed activity cliffs showed no evidence of further chemical exploration.
- Potency progression was detected for approximately 25% of activity cliffs.
- Positive cliff progression, often involving multiple analogues, was observed for about 15% of all activity cliffs.
Conclusions:
- A significant portion of activity cliffs remain chemically unexplored, representing missed opportunities in medicinal chemistry.
- Chemically unexplored activity cliffs present substantial potential for future drug discovery and optimization efforts.
- Further investigation into activity cliffs can accelerate the identification of potent drug candidates.
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