A Broad Panel Of Activities
Studying the Activity of the Thioureas
A Broad Panel Of Activities For a Traditional Scaffold
This paper examines how the Heatmap and pX values in Reaxys® Medicinal Chemistry reveal multiple target families for a whole range of drugs with the thiourea scaffold, which seem particularly potent against GPCRs and kinases.
Applying in silico profiling makes it easier to determine the full panel of a compound’s activities.
Thiourea is a very simple motif (Figure 1) that is present in a significant number of drugs, including monastrol, thioperamide, metiamide, burimamide, thiopental and capsazepine. However, some thiourea-based compounds are also well-known toxicophores, implicated in pulmonary toxicity and dermatitis. Substituted thioureas are generally less toxic.
Like many of the traditional medicinal chemistry scaffolds, drugs based on thiourea can affect multiple targets. The range of activities displayed by compounds with the thiourea scaffold can be explained by this polypharmacology.
Applying in silico profiling makes it easier to determine the full panel of a activities of a compound. To illustrate this, in silico profiling was performed for thiourea as a substructure. The profiling technique takes advantage of the vast amount of experimental data already extracted, structured and available in the Reaxys Medicinal Chemistry database.
A substructure search for thiourea returned 201,821 compounds with the relevant scaffold from Reaxys Medicinal Chemistry. These compounds are involved in 392,424 reactions, have 258,644 bioactivities associated with them, show activity against 3,452 targets and were extracted from 56,653 citations.
Understanding the structure–target interactions of thioureas
To facilitate comparisons of bioactivity data from different publications and assay types, all the data points in Reaxys Medicinal Chemistry have pX values. They are calculated by transforming EC50, IC50, Ki, etc. into pEC50= -LogEC50, pIC50 = -LogIC50, pKi = -LogKi, etc. These are normalized values assigned to the data to enable straightforward quantification of compound–target affinity regardless of the origin of the data.
The Reaxys Medicinal Chemistry Heatmap (Figure 2) visualizes the relationships between compounds and their targets in terms of key parameters, allowing rapid identification of relevant interactions. The figure shows a section of the activity profile for the most potent thioureas, for which in vitro biological data has been mined from the literature and their associated target proteins. Most potent means a pX above 8.0 (affinity < 10 nM). Here, there are 1,660 benzodiazepines active against 262 targets.
Reading the Heatmap
In the Heatmap, biological affinities or activities are quantified with the aforementioned pX values which range from 1, indicating low activity and displayed in blue, to 15, indicating high activity and displayed in red. The color of the Heatmap cells represent the maximal pX retrieved for a given thiourea compound (row) against a given target (column). Grey cells indicate that qualitative data is available; white cells indicate a lack of data.
The thumbnail provides an overview of the entire Heatmap with a panel highlighting the section of the map currently displayed on your screen and the data density display showing the number of molecules retrieved per target.
Analyzing the dataset is facilitated by means of the data density display, which permits the viewing of the number of molecules retrieved per target. The most common target here is carbonic anhydrase 2. Figure 3 shows how the Heatmap density display can be used to identify the most potent compound against this target.