Modeling of activity landscapes for drug discovery

Activity landscapes (ALs) are graphical representations that integrate compound structure and potency relationships. These computer-generated models enable the interactive large-scale analysis of structure-activity relationships (SARs) and complement traditional approaches to study SARs of individual compound series in a qualitative or quantitative manner. A variety of AL designs have been reported.

The concept of activity landscapes is introduced and different methodologies to represent 2D or 3D AL representations of large compound data sets are described on the basis of original literature references. Several AL variants and extensions have been generated for special applications in medicinal chemistry. These include, for example, AL views of evolving data sets with constant topology, selectivity landscapes and multi-target ALs, or molecular mechanism and multi-property maps. Furthermore, the applicability domain of the AL concept is discussed including specific requirements for practical utility in medicinal chemistry opportunities for further developments.

AL modeling has substantially extended conventional ways to study SARs. The AL concept is inseparable from the notion of activity cliffs that are of high interest in SAR analysis. AL design is an area of active research at the interface between chemoinformatics and medicinal chemistry with potential for further growth. Special emphasis must be put on increasing the usability of AL models for practicing medicinal chemists.