Abstract
Compounds with multitarget activity are of high interest for polypharmacological drug discovery. Such promiscuous compounds might be active against closely related target proteins from the same family or against distantly related or unrelated targets. Compounds with activity against distinct targets are not only of interest for polypharmacology but also to better understand how small molecules might form specific interactions in different binding site environments. We have aimed to identify compounds with activity against drug targets from different classes. To these ends, a systematic analysis of public biological screening data was carried out. Care was taken to exclude compounds from further consideration that were prone to experimental artifacts and false positive activity readouts. Extensively assayed compounds were identified and found to contain molecules that were consistently inactive in all assays, active against a single target, or promiscuous. The latter included more than 1000 compounds that were active against 10 or more targets from different classes. These multiclass ligands were further analyzed and exemplary compounds were found in X-ray structures of complexes with distinct targets. Our collection of multiclass ligands should be of interest for pharmaceutical applications and further exploration of binding characteristics at the molecular level. Therefore, these highly promiscuous compounds are made publicly available.
Highlights
Over the past decade, pharmaceutically relevant compounds with multitarget activity have been experiencing increasing attention
We found that 8011 promiscuous compounds (~20%) were exclusively active against multiple targets belonging to the same class, all of them were tested against proteins from at least seven different classes
The findings illustrated in Figure 4; Figure 5 indicated that the set of multiclass ligands we identified was rich in associated structure–promiscuity relationship information, providing many opportunities for follow-up investigations
Summary
Pharmaceutically relevant compounds with multitarget activity have been experiencing increasing attention. This has resulted from mounting evidence that the efficacy of drugs often depends on engagement of multiple targets in vivo, which is referred to as polypharmacology [1,2,3,4,5]. In this context, multitarget activity is known as promiscuity [6]. The molecular basis of multitarget activity is not well understood, insights from X-ray structures of complexes involving promiscuous compounds are beginning to emerge [7]
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