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