Abstract
Activity cliffs are formed by pairs or groups of structurally similar or analogous active compounds with large differences in potency. They can be defined in two or three dimensions by comparing graph-based molecular representations or compound binding modes, respectively. Through systematic analysis of publicly available compound activity data and ligand-target X-ray structures we have in a series of studies determined all currently available two- and three-dimensional activity cliffs (2D- and 3D-cliffs, respectively). Furthermore, we have systematically searched for 2D extensions of 3D-cliffs. Herein, we specify different categories of activity cliffs we have explored and introduce an open access data deposition in ZENODO (doi: 10.5281/zenodo.18490) that makes the entire knowledge base of current activity cliffs freely available in an organized form.
Highlights
The activity cliff concept has experienced increasing interest in chemical informatics and medicinal chemistry[1,2,3,4,5]
An matched molecular pair (MMP) is defined as a pair of compounds that are only distinguished by a structural change at a single site[7], i.e., the exchange of a substructure, termed a chemical transformation[8]
Data availability The activity cliff information described above is made freely available in four separate data files containing 2D-cliffs, 3D-cliffs, 3D-cliff-MMP extensions, and superpositions of complex X-ray structures and 3D ligands for selected targets: (1) 2D-Cliffs_and_Cliff-Clusters.xlsx (Excel format): 2D-cliffs and clusters belonging to different categories are separately recorded using ChEMBL IDs
Summary
The activity cliff concept has experienced increasing interest in chemical informatics and medicinal chemistry[1,2,3,4,5]. A consensus definition of activity cliffs[1,2,3,4] refers to pairs or groups of structurally similar or analogous active compounds with large differences in potency[4,5]. In addition to 2D-cliffs, three-dimensional activity cliffs (3D-cliffs) can be defined by comparing compound binding modes in X-ray structures[12] This requires the superposition of structures of a given target available in different crystallographic ligandtarget complexes and the assessment of the 3D similarity of bound ligands[12]. Three-dimensional activity cliffs can be further extended by taking 2D ligand information into account This can be accomplished by systematically searching compound activity classes for analogs of 3D-cliff partners[13]. 2D extensions of 3D-cliffs bridge different applications in medicinal and computational chemistry and help to identify candidate compounds for further analysis
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