title: Do medicinal chemists learn from activity cliffs? A systematic evaluation of cliff progression in evolving compound data sets.
abstract: Activity cliffs are defined as pairs of structurally similar compounds with a significant difference in potency. These compound pairs have high SAR information content because they represent small structural changes leading to large potency alterations. Accordingly, activity cliffs are of prime interest for SAR exploration and compound optimization. It is currently unknown to what extent activity cliff information is utilized in practical medicinal chemistry. Therefore, we have assembled 56 compound data sets that evolved over time and searched for analogues of activity cliff-forming compounds with further increased potency. For ∼75% of all activity cliffs, there was no evidence for further chemical exploration. For ∼25% of all cliffs, potency progression was detected. In total, for ∼15% of all activity cliffs, positive cliff progression was observed that often involved multiple analogues. Given these findings, chemically unexplored activity cliffs should provide significant opportunities for further study in medicinal chemistry.
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität , Dahlmannstrasse 2, D-53113 Bonn, Germany.
authors.forename: Dilyana
authors.initials: D
authors.lastname: Dimova
authors.forename: Kathrin
authors.initials: K
authors.lastname: Heikamp
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stumpfe
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations