An Example Of In Silico Profiling part 2


An activity profile for structures that are similar to the hypothetical compound with high potency (pX > 8.0) against their associated targets can easily be generated and visualized using a Heatmap (Figure 3). This type of analysis is essential to understand the risk of off-target effects at a potential active therapeutic dose. In this case, 22 similar substances with a pX above 8.0 (affinity < 10 nM) showed activity against 14 targets.

Figure 3 | Industry Insights Article
Figure 3. Heatmap for compounds with similar structures to the hypothetical hit compound and pX activity above 8.0 (affinity < 10 nM).

On further examination with Reaxys Analysis View, structures similar to the hypothetical hit compound are indeed found to be active on the desired target, namely the histamine receptors, in particular H1 and H3 (Figure 4A).

The histamine receptors are part of the GPCR target family. Investigating which other GPCRs have highly potent binders similar to the hypothetical hit could identify potential selectivity issues early in the drug discovery program (Figure 4B). The 5-HT1A receptor, the dopamine receptors D2 and D4 and the chemokine receptors CCR1 and CCR2 are all indicated from the analysis as potential off-targets within the GPCR target family.

In addition to the GPCR target family, there are similar structures to the hypothetical hit with high activity against the following targets: reverse transcriptase; the sigma 1 receptor; and the progesterone receptor (Figure 4B). These off-target interactions are associated with a broad range of effects, including those of antiretroviral drugs, antipsychotic medications and antiprogestins.

Figure 4A

Figure 4a | Industry Insights Article

Figure 4B

Figure 4b | Industry Insights Article
Figure 4. (A) Analysis View shows the number of similar structures with activity against each target that has a pX value above 8.0 (affinity < 10 nM). (B) Close up of histogram B. The desired targets are grey, while those in red could lead to off-target effects.