Affinity-Based Analytical Platforms for Ligand Screening from Natural Products: Advances, Challenges and Future Perspectives

Natural products represent a valuable source of bioactive molecules; however, efficient discovery of active constituents from complex natural matrices remains a major analytical challenge. Affinity ligand screening integrates molecular recognition with advanced analytical technologies, enabling target-oriented discovery beyond conventional separation-based approaches. This review summarizes recent advances in affinity ligand screening for natural product research, with emphasis on the transition from affinity capture to interaction characterization. Current strategies are classified into three major platforms: non-immobilized affinity screening, immobilized affinity screening, and sensor-based analytical strategies. Non-immobilized approaches better preserve native target conformations, whereas immobilized systems facilitate selective enrichment, target reuse, and high-throughput analysis. Emerging biosensing technologies, including surface plasmon resonance, biolayer interferometry, fluorescence sensing, and electrochemical sensing, enable real-time monitoring and kinetic characterization of ligand–target interactions. The integration of affinity enrichment, mass spectrometry, biochromatography, and biosensing is further transforming ligand screening from hit identification toward mechanism-guided discovery. Current challenges include target stability, weak-binding ligand detection, matrix interference, and limited mechanistic interpretation. Future developments will likely emphasize microfluidic integration, multi-target analysis, intelligent data processing, and multidimensional analytical platforms for more reliable characterization of bioactive constituents from complex natural products.