Non-canonical σ-hole interactions: halogen, chalcogen, and pnictogen bonds in biomolecular structure and drug design

σ-Hole interactions, including halogen, chalcogen, and pnictogen bonds, are a versatile and directional class of noncovalent forces that expand the molecular design space in chemical biology and medicinal chemistry. Their emerging roles in biological systems and medicinal chemistry are now becoming increasingly intriguing, opening new avenues for exploration and this review focuses on the role of these interactions in biological system. Halogen bonds contribute measurably to binding in desolvated protein pockets. Chalcogen bonds stabilize protein structures, control conformation, enable catalysis, and facilitate redox-responsive drug delivery. Pnictogen bonds (PnB) combine electrostatic and orbital components, supporting supramolecular assembly, anion recognition, and selective catalysis, though careful attention to toxicity and ADME properties is required. Early consideration of developability limitations, such as lipophilicity, metabolism, and toxicity, is critical. Increasing attention to σ-hole interactions, combined with polarizable force fields and machine learning structural analysis allows these interactions to be used as predictive and reproducible tools in molecular design. • Comprehensive overview of halogen, chalcogen and pnictogen σ-hole interactions in biology. • Highlights σ-hole roles in drug design beyond classical hydrogen bond and π-bonding. • Integrates structural surveys with computational and medicinal insights.