Studying the Activity of the Thioureas


Based on the density display, it is straightforward to identify the compounds in each target family with pX values above 8.0. Figures 4–9 show the distribution of compounds per target family. Figure 4 shows that GPCRs were the dominant target family, with 19 targets having more than 10 thioureas active against each. In the ion channel (Figure 5) and nuclear receptor (Figure 6) target families, only 2 targets had more than 10 thioureas with potent activity against them. Four protease targets (Figure 7) and 7 kinase targets (Figure 8) had more than 10 thioureas with such high affinity. There were also several targets that do not belong to any of these families with more than 10 thioureas showing potent activity against them (Figure 9).

Studying the Activity of the Thioureas Figure 4 | Elsevier Whitepaper
Figure 4. The number of thioureas with pX values above 8.0 for each of the listed GPCR targets. Only targets with over 10 compounds active against them are shown.
Studying the Activity of the Thioureas Figure 5 | Elsevier Whitepaper
Figure 5. The number of thioureas with pX values above 8.0 for each of the listed ion channel targets. Only targets with over 10 compounds active against them are shown.
Studying the Activity of the Thioureas Figure 6 | Elsevier Whitepaper
Figure 6. The number of thioureas with pX values above 8.0 for each of the listed nuclear receptor targets. Only targets with over 10 compounds active against them are shown.
Studying the Activity of the Thioureas Figure 7 | Elsevier Whitepaper
Figure 7. The number of thioureas with pX values above 8.0 for each of the listed protease targets. Only targets with over 10 compounds active against them are shown.
Studying the Activity of the Thioureas Figure 8 | Elsevier Whitepaper
Figure 8. The number of thioureas with pX values above 8.0 for each of the listed kinase targets. Only targets with over 10 compounds active against them are shown.
Studying the Activity of the Thioureas Figure 9 | Elsevier Whitepaper
Figure 9. The number of thioureas with pX values above 8.0 for each of the listed targets, which do not fall into the GPCR, ion channel, nuclease receptor, protease and kinase families. Only targets with over 10 compounds active against them are shown.

Figure 10 shows a selection of the compounds with their corresponding target and target family. It highlights the diversity of compounds with the thiourea scaffold. A high degree of activity was achieved with a variety of thiourea substitution patterns and cyclic structures.

Studying the Activity of the Thioureas Figure 10 | Elsevier Whitepaper
Figure 10. Thioureas with pX activities above 8.0 against the listed target (thiourea scaffold highlighted in red).

Conclusion

The core thiourea chemical scaffold is present in drugs with a broad range of activity against multiple target families, principally the GPCRs and kinases. Interestingly, the full structure of the molecules exhibiting the highest activity against the most prevalent targets varied significantly despite the common core scaffold. This highlights that thioureas are highly versatile and druggable scaffolds.
This study demonstrates that in silico profiling using Reaxys Medicinal Chemistry is an efficient and rapid method to assess the polypharmacology of thiourea-containing compounds. The same methodology could of course be used to revisit the mechanism of action associated with any traditional medicinal chemistry scaffold.

Essential drug discovery solution

Reaxys Medicinal Chemistry is an extensive database containing chemical information linked to in vitro and in vivo biological activities extracted from over 300,000 articles, 90,000 patents and 5,000 journals. More than 6 million chemical compounds are associated with their biological data (> 29 million bioactivity data points) and linked to information on 12,700 pharmacological targets, allowing the scientists to reveal connections between compounds, effects and targets. The data is indexed and normalized for maximum searchability and consistency.