Compound promiscuity: what can we learn from current data?

• Published in: Drug discovery today Vol. 18; no. 13-14; pp. 644 - 650
• Main Authors: Hu, Ye, Bajorath, Jürgen
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2013
• Subjects: Animals; Drug Discovery - methods; Drug Repositioning; Drug-Related Side Effects and Adverse Reactions; Humans; Ligands; Molecular Structure; Molecular Targeted Therapy; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2013.03.002

•Different investigations have firmly established that many active compounds interact with multiple targets.•In most cases, targets of promiscuous compounds are related to each other; compound promiscuity across different target families is rare.•The stringency of data selection criteria and data confidence levels plays a critically important role for the outcome of compound promiscuity analysis.•Compound promiscuity shows a strong dependence on the type of activity measurements; current growth in promiscuity largely results from the use of approximate assay-dependent activity data. The specificity paradigm that assigns central relevance to achieving target specificity of drug candidates has recently been revisited. Evidence is mounting that polypharmacological drug behavior is often responsible for therapeutic efficacy suggesting the consideration of new drug development strategies. Target promiscuity of compounds is at the origin of polypharmacology. For many bioactive compounds, multiple target annotations are available indicating that compound promiscuity is a general phenomenon. However, careful analysis of compound activity data reveals that the degree of apparent promiscuity is strongly influenced by data selection criteria and the type of activity measurements that are considered. Furthermore, promiscuity involving unrelated targets is less common. Apparent target promiscuity might often better be interpreted as activity promiscuity in different assays.