Pharmacologically Promiscuous Compounds

To avoid confusion, here we use the term pharmacologically promiscuous compound to refer to compounds that are truly active on several drug targets and the term screening artifact to describe compounds that are active in an assay for any reason other than specific activity toward the protein target of interest. 

When a compound interferes with an assay such that it leads to an apparently positive result, this is a screening artifact. There are various possible mechanisms of assay interference, and it is therefore important to understand the screening assay(s) and 

Another source of nonspecific behavior can be observed in cellular assays [65], when a compound does not interfere with the (overexpressed) investigated target but does interfere with a different cellular target, and this result ultimately cascades down to the same assay readout. An example is the measurement of the activity of an overexpressed GPCR by monitoring intracellular Ca levels with Ca -sensitive dyes [66, 67]. If the compound stimulates an endogenous wild-type receptor that also leads to Ca mobilization, then this compound will show up (artifactually) as active 

Target/Mode of Multiple targets. Single target, selec- 

Action multivalent, block target tive, modulate target 

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It can however be used in a standardized profiling panel calibrated against known promiscuous compounds. The THR classification given above is used in the Novartis in vitro safety pharmacology profiling panel where >50 targets have been tested. 

It is important to point out that when a compound is pharmacologically promiscuous in a panel of 50 diverse targets, it is highly likely that the compound also hits several additional targets which are not included in the panel, thereby further increasing the liability risk. The reasons why certain compounds are more promiscuous than others and how promiscuity can be avoided is discussed in Chapter 13. 

Peters, J.-U., Schnider, P., Mattel, P and Kansy M. (2009) Pharmacological promiscuity dependence on compound properties and target specificity in a set of recent Roche compounds. ChemMedChem, 4, 680-686. 

Meta Analysis of Safety Pharmacology Data Predicting Compound Promiscuity 13.2.1... 

The identification of chemical features that cause compounds to be either selective or promiscuous is essential for predictive safety pharmacology methods to inform medicinal chemistry decisions. Therefore an analysis using Bayesian models along with ECFP descriptors was used. By using the compound annotation from the previous step, a multicategory Bayes model can be trained. The protocol is as follows ... 

Figure 8.5 BioPrint cluster analysis of 2000 compounds and drugs across 70 pharmacological assays (pICsos). Biological assays are on the x-axis, clustered by similarity, and compounds on they-axis, clustered by their fingerprint of biological activity. Red indicates most active and blue indicates inactive (Reprinted with permission from, Hopkins, et al. Can we rationally design promiscuous drugs Curr. Opin. Struct. Biol., 16, 127-136, copyright 2006, Elsevier.)...

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