Pleiotropic ligands at recombinant human targets retrieved from the PDSP Ki database: Comparative analysis of binding affinities, functional profiles, and screening of clinical relevance by therapeutic plasma concentrations
Lilly Josephine Bindel, Roland Seifert · Journal of Pharmacology and Experimental Therapeutics · 2026
Pleiotropic ligands interact with multiple pharmacological targets, contributing to desired therapeutic but also adverse effects. This mini-review identifies pleiotropic compounds and integrates ligand binding affinities from the PDSP K i database with target classification, therapeutic plasma concentrations, functional annotations from the IUPHAR/BPS Guide to Pharmacology, and stereoisomer-specific comparisons. Compounds were included if potential target binding at recombinant human systems were reported for at least 10 targets (pK i > 5). In total, 253 pleiotropic ligands were identified, including 72 approved drugs, 6 active metabolites, two endogenous ligands, and 170 research compounds. These ligands covered 4447 relevant bindings, mainly at GPCRs (79.6%), followed by kinases (12.2%), transporters (6.5%), ion channels (1.7%), and other protein targets. The number of active targets ranged from 10 to 94, with a median of 14. G protein-coupled receptor (GPCR) binding was dominated by serotonin receptors (5-HT x R), adrenoceptors (AR), and dopamine receptors (D x R), whereas kinase-oriented ligands mainly showed intra-kinase pleiotropy. Therapeutic relevance screening of 74 approved drugs showed that the median number of potentially clinical relevant targets was 9 at the upper therapeutic concentration limit and 7 at the lower limit, indicating concentration-dependent target engagement in several compounds. Comparison with the IUPHAR/BPS Guide to Pharmacology showed both concordance with established targets, but also found targets without curated annotations. The functional profile of mGPCR antagonists confirmed a broad GPCR target spectrum but differed in pK i values and functional behavior. Stereoisomeric data were highly incomplete. Overall, pleiotropic ligand behavior is characterized by target breadth, affinity distribution, functional profile, and therapeutic context.