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.

Abstract

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 Psychoactive Drug Screening Program K_i database with target classification, therapeutic plasma concentrations, functional annotations from the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (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, 2 endogenous ligands, and 170 research compounds. These ligands covered 4,447 relevant bindings, mainly at G-protein coupled receptors (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. GPCR binding was dominated by serotonin receptors (5-HT_xR), adrenoceptors (AR), and dopamine receptors (D_xR), whereas kinase-oriented ligands mainly showed intra-kinase pleiotropy. Therapeutic relevance screening of 74 approved drugs showed that the median number of potentially clinically 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. SIGNIFICANCE STATEMENT: This analysis integrates binding affinities of pleiotropic ligands from the PDSP K_i data base with target classification, therapeutic plasma concentrations, and functional annotations from the IUPHAR/BPS Guide to Pharmacology. Target breadth, affinity distribution, functional behavior, and potential clinical relevance require consideration. For therapeutic compounds, established target annotations do not fully reflect the experimentally reported binding profile, and several non-primary targets may be clinically relevant.