The Versatility of 1,4-Benzodiazepines


Alternative targets

The set of 6,885 1,4-benzodiazepines retrieved from Reaxys Medicinal Chemistry exhibit not only affinity of less than 100 nM for the GABAA receptor but also on a wide variety of other targets (292 alternative proteins). Therefore, a more detailed analysis was performed to show the repartition of compounds per target family (Figures 5 to 9). GPCRs were the most prevalent target family: 26 targets had more than 50 1,4-benzodiazepines active against each of them (Figure 5).

Assessing the Polypharmacology of 1,4-Benzodiazepines Figure 5
Figure 5. Number of 1,4-benzodiazepines with a pX value greater than 7 per GPCR target (only targets with over 50 compounds are shown)
Assessing the Polypharmacology of 1,4-Benzodiazepines Figure 6
Figure 6. Number of 1,4-benzodiazepines with a pX value greater than 7 per ion channel target (only targets with over 50 compounds are shown)
Assessing the Polypharmacology of 1,4-Benzodiazepines Figure 7
Figure 7. Number of 1,4-benzodiazepines with a pX value greater than 7 per protease target (only targets with over 50 compounds are shown)
Assessing the Polypharmacology of 1,4-Benzodiazepines Figure 8
Figure 8. Number of 1,4-benzodiazepines with a pX value greater than 7 per kinase target (only targets with over 50 compounds are shown)
Assessing the Polypharmacology of 1,4-Benzodiazepines Figure 9
Figure 9. Targets other than GPCRs, ion channels, proteases and kinases with over 50 1,4-benzodiazepines active against them with a pX value greater than 7

Some structures containing the 1,4-benzodiazepine core scaffold and active against kinases are shown in Figure 10.

Assessing the Polypharmacology of 1,4-Benzodiazepines Figure 10
Figure 10. The most potent benzodiazepines disclosed in recent patents with pX value greater than 7.0 for different kinases (benzodiazepine scaffold highlighted in red).

Conclusion

The core benzodiazepine chemical scaffold is present in a whole range of compounds with activity against multiple target families, principally the GPCRs, kinases, proteases and ion channels. 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 benzodiazepines 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 benzodiazepine compounds. The same methodology could of course be used to revisit the mechanism of action associated with any traditional medicinal chemistry scaffolds.

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.