What is the Likelihood of an Active Compound to Be Promiscuous? Systematic Assessment of Compound Promiscuity on the Basis of PubChem Confirmatory Bioassay Data
Journal Title: The AAPS Journal - Year 2013, Vol 15, Issue 3
Abstract
Compound promiscuity refers to the ability of small molecules to specifically interact with multiple targets, which represents the origin of polypharmacology. Promiscuity is thought to be a widespread characteristic of pharmaceutically relevant compounds. Yet, the degree of promiscuity among active compounds from different sources remains uncertain. Here, we report a thorough analysis of compound promiscuity on the basis of more than 1,000 PubChem confirmatory bioassays, which yields an upper-limit assessment of promiscuity among active compounds. Because most PubChem compounds have been tested in large numbers of assays, data sparseness has not been a limiting factor for the current analysis. We have determined that there is an overall likelihood of ∼50% of an active PubChem compound to interact with two or more targets. The probability to interact with more than five targets is reduced to 7.6%. On average, an active PubChem compound was found to interact with ∼2.5 targets. Moreover, if only activities consistently detected in all assays available for a given target were considered, this ratio was further reduced to ∼2.3 targets per compound. For comparison, we have also analyzed high-confidence activity data from ChEMBL, the major public repository of compounds from medicinal chemistry, and determined that an active ChEMBL compound interacted on average with only ∼1.5 targets. Taken together, our results indicate that the degree of compound promiscuity is lower than often assumed.
Authors and Affiliations
Ye Hu, Jürgen Bajorath
Keywords
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- DOI 10.1208/s12248-013-9488-0
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