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

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.