Abstract
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.
Highlights
Multitarget activity of small molecules continues to be a much debated topic in drug discovery [1,2].Current views are that many pharmaceutically relevant compounds elicit therapeutic effects in vivo through interactions with multiple targets, a phenomenon referred to as polypharmacology [1,2,3].On the other hand, multitarget activity, termed promiscuity [4], is responsible for undesired side effects
Subsequent activity data analysis was centered on these compounds and emphasis was put on the question of how multitarget ligands (MTLs) from X-ray structures might act across biological screens
We concentrated on the question how confirmed MTLs act across biological screens
Summary
Multitarget activity of small molecules continues to be a much debated topic in drug discovery [1,2].Current views are that many pharmaceutically relevant compounds elicit therapeutic effects in vivo through interactions with multiple targets, a phenomenon referred to as polypharmacology [1,2,3].On the other hand, multitarget activity, termed promiscuity [4], is responsible for undesired side effects. Systematic analysis of in vitro compound activity data can be carried out to estimate promiscuity on a large scale [3,4,5]. Activity data analysis is inevitably affected by data incompleteness, since available small molecules will hardly ever be tested against all potential pharmaceutical targets [5]. On the basis of currently available activity data, bioactive compounds are generally less promiscuous than often assumed [5,10]. Large numbers of compounds with confirmed activity against proteins from different families or classes have been identified on the basis of assay data [11] and publicly available X-ray structures of Molecules 2020, 25, 794; doi:10.3390/molecules25040794 www.mdpi.com/journal/molecules.
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