Biological Activity Profiles of Multitarget Ligands from X-ray Structures

In pharmaceutical research, compounds with multitarget activity receive increasing attention. Such promiscuous chemical entities are prime candidates for polypharmacology, but also prone to causing undesired side effects. In addition, understanding the molecular basis and magnitude of multitarget activity is a stimulating topic for exploratory research. Computationally, compound promiscuity can be estimated through large-scale analysis of activity data. To these ends, it is critically important to take data confidence criteria and data consistency across different sources into consideration. Especially the consistency aspect has thus far only been little investigated. Therefore, we have systematically determined activity annotations and profiles of known multitarget ligands (MTLs) on the basis of activity data from different sources. All MTLs used were confirmed by X-ray crystallography of complexes with multiple targets. One of the key questions underlying our analysis has been how MTLs act in biological screens. The results of our analysis revealed significant variations of MTL activity profiles originating from different data sources. Such variations must be carefully considered in promiscuity analysis. Our study raises awareness of these issues and provides guidance for large-scale activity data analysis.