GPCR ligands

An example, where different receptor subtype selectivities have been observed for chemically related compounds, is presented in Fig. 3.7. The 5-HT3 receptor is a serotonin-controlled ion channel, whereas the 5-HT4 receptor is, like all other serotonin receptor subtypes, a GPCR. Despite a close chemical similarity, compound 31 is highly specific for the 5-HT3 receptor, having a more than 300-fold higher affinity to the 5-HT3 ion channel than to the 5-HT4 receptor (FQ 5-HT3 = 3.7 nM versus FQ 5-HT4 1000 nM selectivity 250), while compound 32 binds almost exclusively to the 5-HT4 receptor (FQ 5-HT3 10 000 nM versus FQ 5-HT4 = 13.7 nM selectivity 700) [30,31], 

Sources Textbooks of Medicinal Chemistry, Annual Reports of Medicinal Chemistry. 

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Figure 16.2 GPCR ligands from virtual screening.

HGnn, J. Maigret, B. Tarek, M. Escrieut, C. Fourmy, D. Chipot, C., Probing a model of a GPCR/ligand complex in an explicit membrane environment. The human cholecystokinin-1 receptor, Biophys. J. 2006, 90, 1232-1240. 

Table 1 Most frequent unique structural features of GPCR ligands by class...

GPCR Substructure Frequency in class (%) Frequency in other GPCR ligands (%)... 

It can be shown that the unsupervised learning methodology based on Kohonen self-organizing maps algorithm can be effectively used for differentiation between various receptor-specific groups of GPCR ligands. The method is similar to that described in Section 12.2.6. 

Fig. 12.11 3-D diagrams of distribution of three target-specific groups of GPCR ligands...

In general, reagent-based selection is much faster and more convenient to execute in the laboratory as compared with the product-based selection. On the other hand, the latter strategy usually provides more accurate results. There exists a potential to combine both approaches to achieve more optimal results, particularly in the case of large exploratory virtual combinatorial libraries, for which mass random synthesis and screening are not economically feasible. In this article, we demonstrated the usefulness of property-based approach for selection of optimal GPCR ligands. 

Moro S, Spalluto G, Jacobson KA (2005) Techniques Recent developments in computer-aided engineering of GPCR ligands using the human adenosine A3 receptor as an example. Trends Pharmacol Sci 26 44-51... 

G-protein coupled receptor (GPCR)—ligand binding assays... 

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