Re-Examining the Potential of Barbiturates
Understanding The Structure–Activity Relationships Of Barbiturates
Derivatives of barbituric acid have diminished in popularity as drugs over the years. Are there really no new indications for these compounds? This paper examines how the pX values in Reaxys® Medicinal Chemistry reveal more about the structure–activity relationships of compounds with this classical medicinal chemistry scaffold.
In silico profiling can provide new insights into a drug’s action and suggest new indications.
Most traditional drugs act on more than one target. Their range of therapeutic action is at least partially explained by this complex, multifaceted pharmacological behavior. Assessing the classic medicinal chemistry scaffolds to establish their range of structure–activity relationships can provide new insights into a drug’s action and suggest new indications. In silico profiling provides a powerful means to rapidly and efficiently assess a compound’s polypharmacological profile.
In this study, in silico profiling was performed on barbiturates, a classical medicinal chemistry scaffold. The profiling technique takes advantage of the vast amount of experimental data already extracted, structured and available in the Reaxys Medicinal Chemistry database.
The applications of barbituric acid derivatives
Derivatives of barbituric acid (Figure 1) exhibit hypnotic, anesthetic and anticonvulsant effects. While they were widely used in the past, benzodiazepines and new classes of hypnotics, such as imidazopyridines, have supplanted them to a large degree. Today the use of barbiturates such as phenobarbital is restricted to the treatment of severe seizures and some protocols for anesthesia.
A substructure search for barbituric acid returned 19,851 compounds with the relevant scaffold from Reaxys Medicinal Chemistry. These compounds are involved in 31,045 reactions, have 43,066 bioactivities associated with them, show activity against 546 targets and were extracted from 8,406 citations.
Understanding the structure–Activity Relationships Of Barbiturates
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 visualizes the relationships between compounds and their targets in terms of key parameters, allowing rapid identification of relevant interactions. If in vitro biological data has been mined from the literature for a compound, it can be displayed using this feature. Figure 2 shows a section of the Heatmap for the barbiturates with a pX value above 8.0 (affinity < 10 nM) and the target protein associated with that compound. In this case, there are 208 barbiturates active against 13 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 barbiturate compound (line) 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.
Reaxys Analysis View is a paired histogram-based analytical tool that lets users select analysis criteria to get a sense of the relationships between results. For example, it permits quick discovery of the individuals and organizations that are active in a particular area of research, sorts results according to yield, or reveals the catalysts or solvents for a particular reaction class.
Here, it has been used to view the number of molecules retrieved per target (Figure 3). The top 6 most common targets with pX values greater than 8.0 (affinity < 10 nM) were MMP-13 (91 occurrences), MET kinase (58 occurrences), MMP-9 (37 occurrences), MMP-2 (30 occurrences), MMP-8 (18 occurrences) and ADAM-17 (5 occurrences). The majority of barbituric molecules are active on proteases, such as MMP-13, MMP-9, MMP-2, MMP-8 and ADAM-17, in the 10 nM or lower range.
Figure 4 shows the structures of the most active barbiturates for MMP-13 (a protease), ADAM-17 (a protease), MET (a kinase) and nicotinic acetylcholine (an ion channel).