1. Systematic identification and characterization of compounds with reliable activity against multiple target proteins from different classes
- Author
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Sanjana Srinivasan and Jürgen Bajorath
- Subjects
Multi-target compounds ,Polypharmacology ,Structural relationships ,Protein classes ,Unrelated targets ,Compound-based target relationships ,Chemistry ,QD1-999 - Abstract
Polypharmacology provides a basis for the treatment of diseases originating from perturbed target and pathway networks. It depends on the use of compounds with suitable multi-target activity and pharmacological effects resulting from multi-target engagement. In addition to their central role for polypharmacology, multi-target compounds are also of interest for basic research, for example, to better understand their binding characteristics or interaction patterns. While it is not unlikely that active compounds might bind to closely related targets, we have been interested in identifying compounds that are active against distantly or unrelated proteins, representing more unexpected instances of multi-target activity. Therefore, we have carried out a systematic search for compounds with activity against proteins from different classes, termed multi-class compounds (MC-CPDs). To this end, currently available compound activity data from medicinal chemistry were carefully curated. Subsequent analysis of ∼120,000 qualifying compounds with high-confidence target annotations identified 689 MC-CPDs with activity against at least three targets from two different protein classes. The target distribution of these compounds was determined and structural relationships were explored together with activity profiles. MC-CPDs covered many target combinations and established a wealth of compound-based target relationships, some of which could be rationalized by considering ligand binding characteristics of distinct targets. As a part of our study, the collection of newly identified MC-CPDs and associated target information is made publicly available.
- Published
- 2024
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