Integrated Screening Cascades for Ion-Channel Drug Discovery: Linking Structure, Electrophysiology, Safety Pharmacology, and Human-Relevant Models.

Ion channels are validated drug targets, but they remain difficult to study as their pharmacology is influenced by rapid gating, conformational state transitions, cell-type-specific expression, and narrow safety margins. Recent advances in cryo-electron microscopy, structure-based in silico screening, machine-learning-guided prioritization, optical high-throughput screening, automated patch-clamp electrophysiology, and human-relevant organoid or microphysiological system (MPS) models are transforming this field. In this expanded review, we examine how these modalities can be integrated into a hybrid discovery pipeline that begins with computational triage, proceeds through scalable functional screening and state-aware electrophysiological validation, and concludes with multi-channel safety de-risking and translational analysis in complex human models. We also discuss disease-associated channel remodeling in cancer and inflammatory disorders, with an emphasis on transient receptor potential channels, voltage-gated potassium channel 1.3 (Kv1.3), Piezo channels, transmembrane protein 16A/anoctamin-1 (TMEM16A/ANO1), chloride channels, and proarrhythmic safety risks. Additionally, we highlight unresolved challenges, including bias in artificial intelligence models, incomplete conformational sampling, assay interference, organoid heterogeneity, and regulatory acceptance of MPS platforms. This review proposes a staged decision framework in which computational prioritization, scalable functional screening, direct electrophysiological confirmation, safety pharmacology, DMPK assessment, and disease-relevant human models serve as complementary filters rather than competing platforms for the identification of selective and translatable ion-channel therapeutics.