Dataset Selection

Application Note

Virtual Screening to Identify Calcium Channel Blockers

Dataset Selection

The first step in the search for a new TCCBs is to collect all pertinent chemical and biological information related to TCCBs, in particular the Cav3.2 isoform (Figure 3). Searching by target name, initially under ion channels and then by narrowing the search down to voltage-dependent calcium channels, followed by selection of the specific isoform enables easy retrieval of all the relevant chemical and biological data from Reaxys Medicinal Chemistry.

Selection of relevant data to retrieve from Reaxys Medicinal Chemistry | Elsevier Whitepaper
Figure 3. Selection of relevant data to retrieve from Reaxys Medicinal Chemistry

To facilitate comparisons of bioactivity data from different publications and assay types, all the data points in Reaxys Medicinal Chemistry have pX values. pX values are calculated by transforming parameters such as EC50, IC50 and Ki into the –Log equivalent (pEC50, pIC50, pKi). These are normalized values assigned to the data that enable easily quantification of compound–target affinity and compare information from all around the world.
The target search for the Cav3.2 isoform of TCCBs in Reaxys Medicinal Chemistry retrieved the chemical structure of 1,854 ligands active against that specific target. These 1,854 ligands have 2,285 bioactivities associated with them and were extracted from 77 citations (Figure 4A).


The Heatmap for all the ligands with activity against the Cav3.2 isoform of TCCBs | R&D Solutions


The Heatmap for ligands with a pX activity above 6.0 - Industry Insights | Elsevier R&D Solutions
Figure 4. A The Heatmap for all the ligands with activity against the Cav3.2 isoform of TCCBs. B The Heatmap for ligands with a pX activity above 6.0 (affinity < 1 μM).

An affinity profile for the most potent ligands active against the Cav3.2 isoform of TCCBs, with pX values greater than 6.0 (affinity < 1 μM), can be generated and viewed as a Heatmap (Figure 4B). The Heatmap visualizes the relationships between ligands and their targets in terms of key parameters, allowing rapid identification of relevant ligand–target interactions. The map displays all ligands with a pX above 6.0 and the associated target TCCB protein for which in vitro biological data has been mined from the literature. In the Heatmap, biological affinities or activities are quantified as a pX value and displayed from 1 (low activity) in blue to 15 (high activity) in red.
At the time of this analysis, this query resulted in 471 ligands with a pX value of above 6.0 (affinity < 1 μM) against the TCCB target. Some of these molecules are depicted in Figure 5. These molecules were then clustered using variable-length Jarvis-Patrick clustering. The query set was narrowed down and the central molecules of resulting clusters and singletons was used for building the 2D pharmacophore in the virtual screening analysis.

Molecules - Industry Insights | Elsevier R&D Solutions
Figure 5. Some representative molecules from the query

A multitude of key parameters can be explored to aid understanding of the ligand−target interactions, such as drug-like grading, in vitro efficacy, in vivo animal models, metabolism, pharmacokinetic and pharmacodynamic data, and clinical use/application, as well as extensive information on the chemical structure itself. For example, Reaxys Medicinal Chemistry can be used to get detailed metabolic data for each compound/ligand (Figure 6). For each data point, the parameter measured, the value, target, target species, tissue/organ, dose and reference are all shown and both quantitative and qualitative results available in the database. This aspect would be particularly beneficial considering that Mibefradil was withdrawn from the market due to the inhibition of cytochrome P450 enzymes 3A4 and 2D6, which had the potential to lead to serious drug−drug interactions.

Number of 1,4 benzodiazepines with a pX value greater than 7 per GPCR target | R&D Solutions
Figure 6. All of the  detailed information on the metabolism of mibefradil can easily be retrieved: the IC50 value for activity against CYP3A4 and CYP2D6 along with the corresponding reference is highlighted.