Cross-pharmacology analysis of G protein-coupled receptors

Abstract

The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included in the cross-pharmacology profile of the different GPCRs changes significantly upon varying the ligand similarity and binding affinity criteria. However, with the exception of muscarinic receptors, aminergic GPCRs distinguish themselves from the rest of the members in the family by their remarkably high levels of pharmacological similarity among them. Clusters of non-GPCR targets related by cross-pharmacology with particular GPCRs are identified and the implications for unwanted side-effects, as well as for repurposing opportunities, discussed.

Figure 1

Cross-pharmacology profiles among (a) GPCR and (b) non-GPCR targets for the adenosine 2B receptor (ADORA2B). All numerical bioactivity data available (pK_i, pIC₅₀, and pEC₅₀) were considered and the criteria for shared ligands were set to d ≤ 0.2 and pAct ≥ 7.0. See text for the definition of the different parameters (L_i, T_i, E_i, B_i and L_e, T_e, E_e, B_e). Description of gene names is available as Supplementary Material.

Figure 2

Changes in the internal, E_i, and external, E_e, cross-pharmacology scores for the histamine H1 receptor (H1R) upon varying distance and bioactivity thresholds. Size of circles reflect the relative number of targets involved in the cross-pharmacology profile of H1R.

Figure 3

Difference between GPCR and non-GPCR cross-pharmacology, E_i − E_e, versus difference in the number of ligands considered to evaluate the respective cross-pharmacology scores, L_i − L_e, under two sets of criteria: (a) d = 0.0 and pAct ≥ 8.0 and (b) d ≤ 0.2 and pAct ≥ 6.0. Description of gene names and subfamily abbreviations is available as Supplementary Material, ○: aminergic GPCRs, □: peptidic GPCRs, Δ: other GPCRs.

Figure 4

Cross-pharmacology network between GPCR targets and a cluster of non-GPCR targets connected by cross-pharmacology to GPCRs. GPCR targets linked share ligands under the criteria of d ≤ 0.2 and pAct ≥ 9.0; non-GPCR targets linked share ligands under the same criteria with the adrenoceptor α_2C (marked with a dashed line). Description of gene names is available as Supplementary Material.